In the past 2022, the FDA has approved only three peptide drugs: Tirzepatide, Lutetium 177Lu Vipivotide Tetraxetan and Terlipressin, of which terlipressin was previously available outside the United States as Glypressin®. There is also literature that classifies Gadopiclenol approved in 2022 as a peptide drug, but this classification is not rigorous. Gadopiclenol contains only an amide bond, but it is not a condensation of two amino acids and should not be considered a peptide.

Trofinetide

Trofinetide is a novel synthetic analog of glypromate, also known as glycine-proline-glutamate (GPE). GPE is an N-terminal tripeptide of a naturally occurring protein and insulin-like growth factor 1 (IGF-1) in the brain. Compared with the proline Cα of GPE, trofinetide has one more methyl group.

Trofinetide (Daybue^TM), developed by Acadia, is a peptide drug approved by the FDA for the treatment of Rett syndrome on March 10, 2023, making it the first FDA-approved Rett syndrome drug in history. Syndrome drugs. Rett syndrome is a rare disease with a spectrum of cognitive, motor, and autonomic symptoms. It is a complex, rare neurodevelopmental disorder usually caused by genetic mutations in the MECP2 gene. It is characterized by a period of normal development before 6 to 18 months of age, followed by significant developmental regression, with loss of acquired communication skills and use of the hands. Symptoms of Rett syndrome may also include hand rigidity, such as wringing and clapping, and abnormal gait. In the United States, Rett syndrome affects 6,000 to 9,000 patients, of whom approximately 4,500 have been diagnosed. The approval of Trofinetide is undoubtedly a milestone event in the history of human struggle against Rett syndrome.

• Mechanism of Action of Trofinetide

Most cases of Rett syndrome are associated with loss-of-function mutations in the gene encoding methyl CpG-binding protein 2 (MECP2). MECP2 is a DNA-binding protein that plays a role in the epigenetic regulation of gene expression. These mutations lead to immature synapses in the cerebral cortex, abnormal metabolism of cholesterol in the brain leading to abnormal neuronal development, and abnormal neuronal signaling. Rett syndrome is more common in girls than boys.

The exact mechanism of action of Trofinetide in Rett syndrome has not been fully elucidated. In mouse studies, GPE peptides improved exercise and cardiorespiratory function, increased brain weight, and extended the lifespan of MECP2-deficient mice. As a synthetic analogue of GPE, trofinetide similarly attenuates apoptosis and reduces infarct size in a dose-dependent manner in a rat model of hypoxic injury. Trofinetide plays a multifaceted role in reducing inflammation, excitotoxic-induced tissue damage and apoptosis, thereby protecting neurons and their surrounding underlying tissues.

Rezafungin

New Echinocandin Peptide Drugs

On March 22, 2023, the FDA approved Cidara and Melinta’s Rezzayo^TM (rezafungin for injection) for the treatment of candidemia and invasive candidiasis in patients 18 years of age or older. Rezafungin is a new generation of broad-spectrum, long-acting echinocandin. Rezafungin has shown effective antifungal activity against Candida, Aspergillus and pneumospora sp. Rezafungin also became the first new echinocandin to receive FDA approval in more than a decade. Unlike other echinocinins such as caspofungin and micafungin, rezafungin has long-acting pharmacokinetics and high stability, allowing it to be administered at long intervals and maintain high plasma exposure. Rezafungin has a half-life of more than 130 hours and can be administered once a week instead of daily.

• Candidemia and Invasive Candidiasis

Candidemia and invasive candidiasis are rare, serious and life-threatening infections. According to the U.S. Centers for Disease Control and Prevention, the average rate of new infections in the United States is about 9 per 100,000 people, or about 25,000 cases per year. These infections are prone to occur in patients who already have other diseases and can lead to high morbidity and mortality. Patients at risk for invasive fungal infections include severely ill patients, immunosuppressed patients, patients after surgery, and patients using central venous catheters. In this already vulnerable patient population, invasive infections with candida often lead to serious illness and death. Patients with these invasive infections may develop a range of comorbidities on top of their underlying disease, including fever and septic shock. An additional hospital stay of 3 to 13 days is estimated after diagnosis of candidemia and invasive candidiasis. In addition, the mortality rate of these infected patients exceeds 40%. Echinocandins are used as first-line antifungals in practice guidelines for candidemia and invasive candidiasis because of their proven efficacy and safety as well as their powerful fungicidal activity.

• Another Cyclic Peptide

Rezafugin was discovered during the development of an orally administered Echinocin. Its outstanding structural feature is its chemical modification, mainly the addition of the choline moiety to the cyclic hexapeptide ring. This significantly improves molecular stability and biological properties. Compared to other echinocinins, the reduced metabolism and degradation of rezafungin enhances its stability and prolongates the half-life of the drug. This made it possible to administer the drug intravenously once a week.

• Mechanism of Action of Rezafungin

Rezafungin is an echinocandin antifungal drug. It inhibits the 1,3-β-D-glucan synthase complex in the fungal cell wall, which is responsible for the formation of 1,3-β-D-glucan. Since 1,3-β-D-glucan is an important component of fungal cell walls, rezafungin disrupts the cell walls of fungal species including Candida and acts as a concentration-dependent fungicide in vitro. Mammalian cells do not express β-1-3-glucan synthase, therefore, the action of rezafungin is specific to fungi.

Posluma (flotufolastat F 18)

Posluma (flotufolastat F 18) is an 18F-labeled ligand and an imaging agent for the detection and localization of prostate cancer in PET (positron emission tomography). Posluma contains an imaging agent (18F) whose active ingredient is flotufolastat F 18 gallium bound to non-radioactive gallium. Flotufolastat F 18 binds to prostate-specific membrane antigen (PSMA) (IC50= 4.4 nM) expressed on cells, including prostate cancer cells. In patients with recurrent prostate cancer who require local treatment, positron emission tomography (PET) with an 18F-labeled ligand provides accurate diagnostic imaging. The 18F group in Flotufolastat is a beta + emitting radionuclide that can be detected using PET. Since prostate cancer cells overexpress PSMA and flotufolastat F-18 is internalized by the cells, this radioactive agent can be used for diagnostic imaging in prostate cancer patients. Posluma received FDA regulatory approval on May 25, 2023 for PET of PSMA-positive lesions in men with suspected metastatic prostate cancer. It is the first FDA-approved PSMA-targeted imaging agent developed using a proprietary radiohybridization technology.

Paxlovid (nirmatrelvir, ritonavir)

The two active substances in Paxlovid, nirmatrelvir and ritonavir, are both peptidomimetics. Nirmatrelvir acts as a protease inhibitor to block the activity of proteases required for virus reproduction. It is an inhibitor of 3C-like protease (3C-like protease, 3CLPRO, also known as Mpro), which plays a key role in the replication of SARS-CoV-2 virus. The second peptidomimetic active substance ritonavir in Paxlovid is used as a pharmacokinetic enhancer of nirmatrelvir, which increases the half-life and bioavailability of nirmatrelvir by inhibiting the degradation of nirmatrelvir by CYP3A4.

Peptide is a type of compound formed by connecting multiple amino acids through peptide bonds, usually composed of 10-100 amino acid molecules, and its connection method is the same as that of protein. The relative molecular mass is less than 10,000. In recent years, with the development and maturity of peptide synthesis technology, peptide drugs have become one of the hot spots of drug research and development. Because of their wide indications, high safety, and remarkable efficacy, they have been widely used in the prevention, diagnosis and treatment of tumors, cardiovascular and cerebrovascular, hepatitis, diabetes, AIDS and other diseases.

Characteristics of peptide drugs

Peptide drugs have high safety and high target affinity. They are mainly eliminated by proteolytic degradation and renal filtration. The products of hydrolysis are amino acids. Therefore, it is generally not considered whether the metabolites of peptide drugs are toxic.

The developed peptide drugs often use endogenous peptides as templates, which usually have a higher target affinity and a smaller risk of off-target.

The probability of peptide drugs being approved for marketing through clinical trials is twice higher than that of small-molecule drugs, and the average R&D cycle is 0.7 years shorter. The development of peptide drugs has also extended to many disease fields, including anti-infection, anti-tumor, physiological regulation, pain, heart failure, osteoporosis, diabetes, vaccines, etc.

Compared with protein, peptide chemical synthesis technology is mature, easy to separate from impurities or by-products, high purity, and easy to introduce unnatural amino acids. However, the quality, purity and yield of recombinant proteins are difficult to guarantee. And the recombinant proteins cannot be introduced with unnatural amino acids and cannot be amidated at the ends. At the same time, the production cycle is long and the cost is high. Peptides are generally lower in cost than protein and antibody drugs, and higher in synthesis cost than most small molecule drugs.

Peptides are easily degraded, have a short half-life and a high plasma clearance rate. The biggest problem with peptides is that they cannot be taken orally, mainly because they are easily degraded and difficult to cross the intestinal mucosa. In addition, peptides are easily hydrolyzed by proteolytic enzymes in the blood after entering the blood, and have a short plasma half-life and plasma clearance rate, which affects the efficacy of the drug and the choice of the route of administration, and therefore does not produce drug accumulation.

Peptide drugs may develop immunogenicity as the number of amino acids increases.

Table 1 Comparison of peptide with small-molecule and protein

Marketed Peptide Drugs

In the future, the number of peptide drugs in the world will continue to increase. There is no shortage of innovations in peptide drugs and they have great potential. In the future, emerging peptide drugs such as antimicrobial peptides, peptide vaccines, peptide carriers, PDC drugs, etc., are still in the clinical research stage and have very good market prospects. Antimicrobial peptides, as new and powerful broad-spectrum antibiotics, are different from previous antibiotics, and have the advantages of improving immunity and not easy to develop drug resistance. Peptide vaccines use certain peptides to have immunogenicity. They are currently on the market in the field of hepatitis treatment, and a new generation of peptide vaccines in the field of Ebola and AIDS are under development.

The therapies that this article focuses on include: peptide coupling therapy, oligonucleotide therapy, antibody therapy, cell therapy, gene therapy, small molecule therapy, etc.; covering diseases involving multiple myeloma, Merkel cell carcinoma, and systemic sclerosis disease-related interstitial lung disease, acute graft-versus-host disease, Fabry disease, retinitis pigmentosa, gangliosidosis, frontotemporal dementia, Krabbe disease, type A molybdenum cofactor deficiency, Alport syndrome chronic kidney disease, Waldenstrom’s macroglobulinemia, Prader-Willi syndrome, spinal muscular atrophy, amyotrophic lateral sclerosis, hereditary angioedema, etc.

Peptide Conjugated Therapy

• Pepaxt

On February 26, Oncopeptides announced that the US FDA has accelerated the approval of Pepaxto (melphalan flufenamide, also known as melflufen) to be marketed in combination with dexamethasone to treat adult patients with specific relapsed/refractory multiple myeloma (MM). Pepaxto is the first anti-cancer peptide conjugate drug approved by the FDA.

MM is a malignant blood cancer caused by abnormal proliferation of plasma cells in the bone marrow. Cancerous plasma cells can affect the production of normal blood cells, leading to decreased blood cell index, bone damage, and kidney damage. Although in the past ten years, the emergence of innovative therapies has significantly revolutionized the treatment of MM. However, many patients with MM will still relapse and develop resistance to existing therapies. Therefore, these patients with relapsed/refractory MM still need new treatment options.

Figure 1: Pepaxto molecular structure.

Pepaxto is a “first-in-class” peptide-conjugated drug that conjugates alkylating agents with peptides that target aminopeptidase. Pepaxto can be quickly taken up by MM cells due to its lipophilicity. In the cell, it will be quickly hydrolyzed by peptidase, thereby releasing the hydrophilic alkylating agent. Aminopeptidase is overexpressed in tumor cells, especially in advanced cancers or tumors with high mutation complexes. In in vitro experiments, Pepaxto can increase the concentration of the alkylating agent in the cell, and its ability to kill MM cells is 50 times higher than that of the alkylating agent it carries.

Oligonucleotide Therapy

• Cavrotolimod (AST-008)

On March 3, Exicure announced that the US FDA granted its oligonucleotide therapy cavrotolimod (AST-008) orphan drug designation (ODD) for the treatment of Merkel cell carcinoma (MCC).

Cavrotolimod (AST-008) is a Toll-like receptor 9 agonists designed to activate the innate immune system and induce an effective anti-cancer immune response, especially when used in combination with checkpoint inhibitors.

Merkel cell carcinoma (MCC), also known as cutaneous neuroendocrine carcinoma, is a rare and highly aggressive tumor that tends to occur at the site of sun damage. MCC is derived from Merkel cells related to touch in superficial skin, and tumor cells contain neuroendocrine granules, so they have neuroendocrine cancer properties. MCC usually occurs on the face, neck, limbs, and other sun-irradiated areas. It is manifested as red skin bulges. The cause of the disease is not completely clear. About 80% of the cases are related to Merkel cell polyomavirus (MCV) infection. The continuous expression of T antigen may be one of its mechanisms.

Antibody Therapy

• Actemra (tocilizumab)

On March 5th, Genentech announced that the US FDA has approved the extended indications of the IL-6 receptor inhibitor Actemra (tocilizumab) for the alleviation of the rate of decline in lung function in adult patients with systemic sclerosis-related interstitial lung disease (SSc-ILD). Actemra is the first biological therapy approved by the FDA for the treatment of this disease.

SSc-ILD is a progressive lung disease in which lung function gradually declines and may be life-threatening. ILD is the leading cause of death in patients with scleroderma. Due to the gradual decline in lung function, the patient’s lungs cannot provide enough oxygen to the heart.

Actemra is a humanized IL-6 receptor antagonist, which has been approved for the treatment of patients with moderate to severe rheumatoid arthritis. This approval is based on the results of a randomized, double-blind, placebo-controlled Phase 3 clinical trial. In this study, compared with patients in the placebo group, patients treated with Actemra had a lower level of reduced forced vital capacity (FVC) at 48 weeks than in the control group. FVC decreased by 14 ml in the Actemra group and 255 ml in the control group.

• Neihulizumab（AbGn-168H）

On March 8, the US FDA granted AltruBio’s immune checkpoint regulator neihulizumab (AbGn-168H) fast track qualification for the treatment of steroid-refractory acute graft-versus-host disease (SR-aGVHD). Neihulizumab has previously obtained orphan drug designation from the US FDA for the treatment of aGVHD.

Graft versus host disease (GVHD) is an important cause of late non-relapse-related deaths after allogeneic hematopoietic stem cell transplantation (HSCT), and it seriously affects the quality of life of patients. The characteristics of GVHD are similar to the symptoms of autoimmune and other immune diseases, and its pathogenesis is not clear. It is currently believed to be mainly related to the negative selection of CD4+ T cells caused by thymus injury after transplantation, imbalance of cytokines in the body, imbalance of T cell ratio, and autoantibodies against the host synthesized by B cell, etc.

Neihulizumab is an immune checkpoint modulator targeting PSGL-1, which can promote the depletion of chronically activated T cells. This mechanism has been evaluated in four autoimmune and inflammatory diseases, and clinical proof of concept and safety has been verified in 170 patients. The Phase 1b multi-dose trial of SR-aGVHD is currently being studied. In addition, research on the first-line aGVHD is also underway.

Cell Therapy

• SIG-007

On March 5, Sigilon Therapeutics announced that the US FDA has granted its cell therapy product SIG-007 orphan drug designation for the treatment of Fabry disease, which has the potential to prolong the release of functional enzymes.

Fabry disease is a rare X-associated hereditary lysosomal storage disease caused by a defect in the activity of α-galactosidase A in the lysosome. The clinical manifestations of the disease are diverse, with burning pain in the extremities of the hands and feet as the common first symptom. In addition, patients will experience symptoms such as low sweating, no sweating, and heat intolerance in childhood, and even unable to live normally in severe cases. As the disease progresses, Fabry disease can also cause serious damage to the patient’s kidneys, heart, brain, nerves, and other organs. If effective treatment is not available, it may be life-threatening in severe cases. The current standard of care for Fabry disease requires intravenous administration, which may require a longer infusion time and may cause potential infusion-related reactions. Although these therapies have helped patients control the disease, long-term exposure has led to serious complications, including impaired kidney function.

SIG-007 consists of cells genetically modified with non-viral vectors to express human α-galactosidase A or AGAL. SIG-007 has the function of potentially sustaining and prolonging the release level of functional enzymes, thereby producing clinical benefits, and reducing the burden of treatment for patients.

• CiPC

On March 10, 2021, CiRC Biosciences announced that the US FDA has granted orphan drug designation (ODD) for chemically induced photoreceptor-like cells (CiPC) for the treatment of retinitis pigmentosa (RP).

RP is a group of hereditary blindness diseases characterized by progressive retinal photoreceptor-like cell apoptosis and pigment epithelial degeneration. Mutations in RP-related gene loci are the cause of the disease. There are various inheritance modes of RP, including autosomal dominant inheritance, autosomal recessive inheritance, and X chromosome-linked inheritance. The worldwide prevalence rate is 1/3,000 to 1/7,000.

CiRC Biosciences is currently advancing the preclinical development of CiPC, which is used for the treatment of advanced RP and the vision restoration of geographic atrophic age-related macular degeneration. A study conducted in a mouse model of RP showed that CiPC can lead to partial recovery of pupil reflex and visual function. The results of the study are published in the 2020 issue of Nature.

Gene Therapy

• PBGM01, PBFT02, PBKR03

On March 8, Passage Bio announced that the US FDA has granted it three fast-track qualifications for researching gene therapy, including PBGM01 for the treatment of GM1 gangliosidosis (GM1); PBFT02 for the treatment of GRN gene mutations Frontotemporal dementia (FTD-GRN); PBKR03 is used to treat Krabbe disease.

Small Molecule Therapy

• Nulibry (Fosdenopterin)

On February 27, the US FDA announced that it had approved Nulibry (fosdenopterin) developed by Origin Biosciences, a subsidiary of BridgeBio Pharma, to reduce the risk of death due to type A molybdenum cofactor deficiency (MoCD).

• Methyl bardoxolone

On March 1, Reata Pharmaceuticals announced that it had submitted a New Drug Application (NDA) for methyl bardoxolone to the US FDA for the treatment of chronic kidney disease (CKD) caused by Alport syndrome.

• Baiyueze (Zebutinib capsule)

On March 2, BeiGene announced that its self-developed BTK inhibitor Baiyueze (Zebutinib Capsule) has been approved by the Canadian Drug Administration for the treatment of patients with Waldenstrom’s macroglobulinemia (WM).

• Tesomet

On March 3, Saniona announced that the US FDA has granted Tesomet orphan drug designation for the treatment of Prader-Willi syndrome (PWS).

• Evrysdi（Risdiplam）

On March 9, Roche announced that the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) has issued a positive review opinion, recommending approval of Evrysdi (risdiplam) for marketing, treatment for more than 2 months, and clinical diagnosis of spinal cord Patients with all types of muscular atrophy (SMA) (type 1, type 2, type 3) or 5q-SMA with 1 to 4 copies of SMN2.

• AMX0035

On March 10, Amylyx Pharmaceuticals announced that it plans to submit a new drug application for the small molecule combination therapy AMX0035 in Canada for the treatment of amyotrophic lateral sclerosis (ALS). This application is expected to be finalized in the first half of 2021.

• Orladeyo（Berotralstat）

On March 11, BioCryst Pharmaceuticals announced that its once-a-day oral therapy Orladeyo (berotralstat) has been granted a French Temporary Authorization for Use (ATU) for the prevention of hereditary angioedema (HAE) in patients 12 years and older. attack.

Glioma is the most common primary central nervous system tumor. Although the incidence is low, the mortality rate is extremely high. Isocitrate dehydrogenase I (IDH1) mutations are highly likely in glioma patients. In patients with low-grade gliomas and patients with secondary glioblastoma, the proportion of IDH1 mutations can reach about 70%, but there is currently no selective treatment for IDH1 mutant gliomas. IDH1 mutations cause significant changes in enzymatic reactions, catalyzing the large-scale conversion of α-ketoglutarate (2-KG) to 2-hydroxyglutarate (2-HG), and cause significant changes in the cell’s metabolic system. IDH1 mutations cause significant metabolic changes, suggesting that tumor cells rely on specific metabolic pathways to complete cell biological processes. Drug interventions targeting the changing metabolic pathways in IDH1 mutations may suggest new treatment options for gliomas.

The study found that after IDH1 mutation, it will catalyze the massive conversion of 2-KG to tumor metabolite 2-HG, while consuming reduced NADPH. NADPH has the effect of eliminating reactive oxygen species (ROS) in the body, and IDH1 mutation weakens its ability to eliminate ROS. In order to maintain the steady state of ROS, other antioxidant pathways will become more active after IDH1 mutation. In vitro studies have found that in IDH1 mutant glioma stem cells (TS603), the expression of genes related to ROS clearance is overall upregulated, and the gene that regulates glutathione synthesis, SLC7A11, is most upregulated. In addition, inhibiting the expression of SLC7A11 gene will affect the synthesis of glutathione, thereby causing the apoptosis of IDH1 mutant glioma cells.

Glutathione anabolism is regulated by the transcription factor Nrf2 and is an important antioxidant metabolic pathway. Inhibiting the transcriptional activity of Nrf2 can reduce glutathione synthesis. Triptolide is a diterpene epoxy compound extracted from Tripterygium wilfordii, which is a highly effective Nrf2 inhibitor. In vivo and in vitro models, it was found that in the IDH1 mutant glioma cells intervened by triptolide, the transcriptional activity of Nrf2 was suppressed, and the expression of genes related to glutathione anabolic metabolism (GCLC, GCLM, and SLC7A11) was significantly down-regulated. The glutathione synthesis pathway is destroyed, and the oxidative damage in the cells increases, which leads to apoptosis and inhibits tumor growth.

The research team found that in IDH1 mutant cancer cells, the glutathione anabolic pathway is very active. Glutathione anabolism is regulated by Nrf2 transcription factor and is an important antioxidant metabolic pathway. In vitro studies have found that inhibiting the transcriptional activity of Nrf2 can reduce the synthesis of glutathione, thereby causing the apoptosis of IDH1 mutant cancer cells. Based on this finding, the research team proposed a new strategy for inhibiting the glutathione metabolic pathway to treat IDH1 mutant glioma.

Triptolide is a diterpene epoxy compound extracted from Tripterygium wilfordii, which is a highly effective Nrf2 inhibitor. In vitro and in vivo models, it was found that in the IDH1 mutant glioma cells intervened by triptolide, the transcriptional activity of Nrf2 was suppressed, and the expressions of GCLC, GCLM and SLC7A11 were down-regulated, thereby disrupting the metabolism of glutathione. The increased oxidative damage leads to apoptosis. This study illustrates the importance of inhibiting the glutathione metabolic pathway regulated by Nrf2 for tumor therapy, and at the same time provides a new idea for the treatment of malignant tumors with IDH1 mutations.

IDH1 mutations are common genetic abnormalities in human malignancies. In addition to gliomas, they are also very common in acute myeloid leukemia, cholangiocarcinoma, and chondrosarcoma. This study illustrates the importance of inhibiting the glutathione metabolic pathway regulated by Nrf2 for tumor therapy, and at the same time provides a new idea for the treatment of malignant tumors with IDH1 mutations.

References:

1. Triptolide suppresses IDH1-mutated malignancy via Nrf2-driven glutathione metabolism. Yu D, Liu Y, Zhou Y, Ruiz-Rodado V, Larion M, Xu G, Yang C.Proc Natl Acad Sci U S A. . In Press: 2020. [ Journal Article]

Novel coronavirus (COVID-19) is known to cause acute respiratory distress syndrome (ARDS), which causes about 50 percent of ARDS deaths despite intensive care and mechanical ventilation. Therefore, patients with coronavirus infection who develop ARDS are at a particularly high risk. Professor Javitt said: “After carefully reviewing the preclinical and clinical data submitted to FDA for IND and orphan drug certification for Aviptadil, we believe that Aviptadil may be a safe and effective ARDS treatment in general, especially for ARDS caused by COVID-19. Due to the rapid expansion of the epidemic and unusual unmet medical needs, we are prepared to start clinical trials as soon as possible so that potentially life-saving treatments can be brought to market as soon as possible. ”

Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by rapid development of diffuse inflammation in the lungs. Symptoms include shortness of breath, shortness of breath and skin cyanosis. A decline in the quality of life is relatively common among survivors. Causes may include viral infection, sepsis, pancreatitis, trauma, pneumonia and inhalation. The underlying mechanism involves diffuse cellular injury, the formation of microscopic balloon barriers in the lungs, dysfunction of surfactant, activation of the immune system and dysfunction in the regulation of blood coagulation. In fact, ARDS can impair the lung’s ability to exchange oxygen and carbon dioxide. The primary treatment includes mechanical ventilation, combined with treatment for the underlying etiology. Ventilation strategies include low flow and low pressure. If oxygenation is still insufficient, alveolar stretching and neuromuscular blockers can be used. The mortality rate of the syndrome ranges from 35% to 50%. Worldwide, ARDS affects more than 3 million people every year.

Aviptadil is a patented dosage form of vasoactive intestinal polypeptide (VIP). VIP was originally developed as a combination of phentolamine and is now sold in Europe for the treatment of erectile dysfunction. It is known that VIP is highly concentrated in the lung and can inhibit a variety of inflammatory cytokines. In 2001, Aviptadil was certified by American FDA Orphan Drug for the treatment of acute respiratory distress syndrome, and in 2005, it was certified for the treatment of pulmonary hypertension. Aviptadil was certified as an orphan drug by the European Drug Administration in 2006 for the treatment of acute lung injury and in 2007 for the treatment of sarcoidosis. Both FDA and EMEA in the United States have issued licenses for new drugs under development in Aviptadil Phase 2 human trials. The University of Freiburg in Germany is currently conducting a clinical study to evaluate the effectiveness of Aviptadil in patients with pulmonary sarcoidosis.

A large number of animal studies have shown that Aviptadil may reduce pulmonary inflammation in a variety of models and edema. Human phase 1b/2 studies (involving a total of 76 patients) have shown that Aviptadil has the potential to relieve bronchospasm, reduce pulmonary hypertension and treat other features of pulmonary inflammation in some cases, including a significant reduction of alpha pro-inflammatory cytokine tumor necrosis factor (TNF–α). Among them, a phase 2 preliminary trial of Aviptadil in 8 ARDS patients showed excellent safety and encouraging signals of potential efficacy.

References

1. Jahangir, M. A., Muheem, A., & Rizvi, M. F. Coronavirus (COVID-19): History, Current Knowledge and Pipeline Medications. Int J Pharm Pharmacol 2020; 4: 140. doi: 10.31531/2581, 3080(2).
2. Keshavarz, A., Kadry, H., Alobaida, A., & Ahsan, F. (2020). Newer approaches and novel drugs for inhalational therapy for pulmonary arterial hypertension. Expert Opinion on Drug Delivery, 1-23.
3. Sommer, N., Ghofrani, A., Pak, O., Bonnet, S., Provencher, S., Sitbon, O., … & Kiely, D. G. (2020). Current and future treatments of pulmonary arterial hypertension. British Journal of Pharmacology.

Semaglutide is a glucagon-like peptide-1 (GLP-1) analog. It is a hormone that induces insulin secretion and is marketed as Ozempic. The once-weekly injection form was approved by the FDA in 2017 for the treatment of type 2 diabetes. To improve compliance and better long-term results, Novo Nordisk has developed Rybelsus, an oral dosage form of semaglutide, which was approved by the FDA in September 2019.

Cardiovascular disease (CVD) is the leading cause of death and disability in patients with type 2 diabetes. Adults with type 2 diabetes are 2 to 4 times more likely to develop CVD than adults without diabetes.

FDA approval for Ozempic is based on the results of the SUSTAIN 6 Cardiovascular Outcome Trial (CVOT), which assesses the cardiovascular safety of adding Ozempic or placebo to standard treatment for adults with type 2 diabetes and diagnosed cardiovascular disease. In the 2-year SUSTAIN 6 trial, Ozempic significantly reduced the risk of cardiovascular death, non-fatal heart attack, or non-fatal stroke three-component MACE endpoint. Compared to placebo, the estimated MACE relative risk reduction was 26% (HR 0.74 [95% CI: 0.58, 0.95], non-inferiority, median observation time 2.1 years, p <0.001), and the primary composite outcome occurred in 6.6% of Ozempic-treated patients and 8.9% of placebo-treated patients. During the trial, the incidence of gastrointestinal adverse events in the Ozempic group was higher than in the placebo group. Most gastrointestinal adverse events occurred during the first 30 weeks.

Semaglutide promotes insulin secretion and inhibits glucagon secretion in a glucose concentration-dependent mechanism, which can greatly improve blood glucose levels in patients with type 2 diabetes, and has a lower risk of hypoglycemia. At the same time, semaglutide can also induce weight loss by reducing appetite and reducing food intake. In addition, semaglutide can significantly reduce the risk of MACE in patients with type 2 diabetes.

Ozempic (semaglutide, injection preparation) is a weekly subcutaneous injection form (0.5mg or 1mg), which is suitable for: as an adjuvant for diet adjustment and exercise to improve blood glucose control in adults with type 2 diabetes. It also reduces the risk of major adverse cardiovascular events in adults with type 2 diabetes who have cardiovascular disease. Ozempic was first approved by the US FDA in December 2017 and is currently available in 25 countries. Obtained FDA approval for the first time in combination with treatment for adults with type 2 diabetes.

Rybelsus (semaglutide, oral tablet) is a once-a-day tablet that contains an excipient SNAC that promotes absorption. The drug is suitable for: As a diet adjustment and exercise and auxiliary medicine, to improve blood glucose control in adults with type 2 diabetes. Rybelsus is the world’s first and only oral GLP-1 receptor agonist. It is administered once daily with two therapeutic doses: 7 mg and 14 mg. Rybelsus was first approved by the US FDA in September 2019 and is currently under review by multiple regulatory agencies.

Novo Nordisk’s Executive Vice President and Chief Scientific Officer Mads Krogsgaard Thomsen said, “We strongly believe in the therapeutic benefits of semaglutide, and this approval marks a major milestone. Ozempic now provides an effective treatment for patients with type 2 diabetes who have cardiovascular disease in the United States, which can lower blood sugar and reduce cardiovascular risk. We are also very happy that the results of the PIONEER 6 study are reflected on the label of Rybelsus. In order to further evaluate the cardiovascular risk reduction of this drug, we are currently conducting a cardiovascular outcome trial SOUL.”

References:

1. Novo Nordisk: Ozempic® superior in lowering blood sugar and weight vs placebo, both in combination with SGLT-2 inhibitors

Figure 1 Scanning electron micrograph of a human T cell

In the current mainstream model, T cells identify potential threats through surface “T cell receptors” (TCR). For example, when viruses and bacteria infect the human body, specific proteins on their surfaces are loaded into a structure called the major histocompatibility complex (MHC) for T cells to recognize. In the past, we know a lot about αβ T cell receptors. It is believed that T cell receptors will bind to MHC or MHC-like molecules in a head-to-head manner, thereby recognizing specific signals from pathogens. In this study, the scientists focused on γδ T cell receptors, a relative of these receptors.

In this new study, the researchers describe a cell population in a class of little-known T cells called γδT cells that recognizes an MHC-like molecule called MR1. Using high-intensity X-ray beams on a synchrotron in Australia, they obtained detailed three-dimensional images of the interaction between γδT cell receptors and MR1, and got interesting results: γδT cell receptors bind under MHC-like molecules for recognition. Dr. Jérôme Le Nours, one of the co-first authors of the study, made a very vivid metaphor: “Imagine that (MHC molecule) is like a flag standing on a cell. We always think the t-cells are sitting on top of the flagpole, reading the message. But what we found is that some t-cells bind to the bottom first.”

These are important details that can change our approach to studying T cell biology in the future. This is important because T cells are a key weapon of our immune system, and understanding how T cells target and act on other cells is critical to using their power to develop immunotherapies that treat diseases such as infections and cancer. Researchers believe that this unusual recognition system is expected to help us understand how TCR binds to target molecules. Given that T cells are an important weapon in the body’s fight against disease, these insights are expected to lead to more effective therapies. Because γδ T cells also play a role in fighting cancer, the existing anti-cancer immunotherapy has the opportunity to be further enhanced.

Dr Nicholas Gherardin, co-first author of the paper and the Doherty Institute at the University of Melbourne, said: “Our research indicates that MR1 is a novel molecular target for γδT cells. These cells play a decisive role in the immune response against infection and cancer, but little is known about how they respond. MR1 may signal γδT cells to indicate the presence of viruses or cancer cells and trigger these cells to trigger a protective immune response. ” Researchers will dig deeper into this mechanism and strive to apply it to the treatment of diseases.

References

1. Jérôme Le Nours et al. A class of γδ T cell receptors recognize the underside of the antigen-presenting molecule MR1. Science, 2019, doi:10.1126/science.aav3900.

The innate immune system constitutes the first line of defense against invading microbial pathogens. TREM-1 (a trigger receptor expressed on myeloid cell-1) is an immunoreceptor expressed on innate immune cells. TREM-1 regulates inflammation and leads to a vigorous immune response. Unlike most inhibitors, TREM-1 based inhibitors have unique therapeutic capabilities. The ability to use immunomodulation can control the cause of the harmful effects observed by the patient, but does not completely eliminate the inflammatory response. Because inflammatory reactions are still necessary, such as for bacterial clearance.

Figure 1 Schematic representation of TLR4–TREM-1 relationship (Jolly et al 2018)

Inotrem found that the TREM-1 pathway is a key factor leading to an imbalance in the inflammatory response. The company has developed an innovative individualized medical approach based on TREM-1 inhibition for indications characterized by acute or chronic inflammatory syndrome. The reported study was an 11-month multicenter Phase IIa clinical trial in which 49 septic shock patients were enrolled in four European countries (Belgium, France, the Netherlands, and Spain). These results provide positive data on the safety and tolerability of Inorem’s primary candidate, nangibotide, in patients with septic shock. Studies have also shown that nangibotide treatment provides a consistent trend for more favorable biological and clinical activity marker evolution in subpopulations of patients with soluble TREM-1 levels above the median value. These results support Inotrem’s personalized medical approach: using soluble TREM-1 levels in the blood as potential biomarkers for identifying patients most likely to benefit from cystic peptide therapy. The results of this clinical trial reinforce previous preclinical and clinical findings, particularly regarding the safety, biological and clinical activity of cyst peptides and the use of sTREM-1 as a companion biomarker for patient selection.

Nangibotide is a preparation of the active ingredient LR12, and LR12 is a chemically synthesized peptide of 12 amino acids in length. LR12 is a specific TREM-1 inhibitor that acts as a decoy receptor and interferes with the binding of TREM-1 to its ligand. In the preclinical septic shock model, nangibotide is able to restore proper inflammatory response, vascular function, and improve survival after septic shock in animals.

References

1. Jolly, L. , Carrasco, K. , Derive, M. , Lemarié, Jérémie, Boufenzer, A. , & Gibot, Sébastien. (2018). Targeted endothelial gene deletion of triggering receptor expressed on myeloid cells-1 protects mice during septic shock. Cardiovascular Research.
2. Parent, M. , Boudier, A. , Maincent, P. , Gibot, S. , Aitoufella, H. , & Boufenzer, A. , et al. (2018). Lr12-peptide quantitation in whole blood by rp-hplc and intrinsic fluorescence detection: validation and pharmacokinetic study. Biomedical Chromatography, 31.

• Scientists are expected to develop a new type of cellular permeable peptide chimera to promote wound healing.

In recent years, cell penetrating peptides as drug delivery carriers have aroused great interest among scientists. They may help develop new therapeutic agents or cosmetics. In general, compounds with a molecular weight greater than 500Da can hardly pass through the biofilm. In a recent study, researchers covalently combined a sequence that promotes wound healing with cellular osmotic peptides to improve the efficiency of drug transport in cell membranes. The new peptides ingested by cells can be conjugated into keratin cells, which can significantly improve drug transport under good tolerance.

• AJP: Intestinal peptide is helpful to improve the success rate of corneal transplantation. 

A recent article published in the journal American Journal of Pathology found for the first time that injecting neuropeptide (VIP), into the eyes of mice could improve the success rate of corneal transplantation. VIP also has other advantages, such as accelerating wound healing, protecting corneal endothelial cells and improving the cleanliness of corneal transplantation. If the treatment is approved, it will help solve the problems of many patients with corneal diseases.

• Cancer Cell: Scientists develop peptide drugs for accurate treatment of prostate cancer.

In a new study recently published in the international academic journal Cancer Cell, researchers from the University of Michigan developed a new treatment strategy that targets genetic mutations in about half of prostate cancer. When the two genes, TMPRSS2 and ERG, are relocated and fused on chromosomes, prostate cancer development is turned on. However, the development of small molecule inhibitors targeting ERG has always been a great challenge.

• Nature journal: Magic peptides that can effectively deal with drug-resistant bacteria. 

Worldwide abuse of antibiotics has received a lot of attention recently. As a result of excessive use of antibiotics, more and more bacteria have developed drug resistance, resulting in the emergence of “superbugs”. At the same time, the development of new antibiotics has not been able to keep pace with the evolution of bacteria. According to the World Health Organization, 10 million people could die of drug-resistant bacteria each year by 2050. In order to update the arsenal of weapons to deal with bacteria, some scientists have taken different measures. Recently, researchers from the Massachusetts Institute of Technology, the University of Brasilia and the University of British Columbia in Canada have designed an antibacterial peptide that can destroy many kinds of bacteria, including drug-resistant bacteria. The results were published in the journal Scientific Reports.

• Tuberculosis: Specific peptides from fungi are expected to treat tuberculosis. 

In a recent study published in the international journal Tuberculosis, scientists from Lund University found that. A special peptide isolated from saprophytic ascomycetes (Pseudoplectania nigrella) is expected to be used as a new antibiotic to inhibit the growth of Mycobacterium tuberculosis.

• Hypertension: Peptides in spirulina may have obvious antihypertensive effect.

In a recent study published in the international journal Hypertension, scientists from institutions such as the University of Rome said that a peptide extracted from spirulina may be able to fight high blood pressure by dilating blood vessels. The results are expected to help researchers develop new treatments for hypertension at a later stage.

• Ang Chem Int Ed: scientists have developed new macrocyclic peptides that are expected to treat Alzheimer’s disease and type 2 diabetes.

At present, researchers have not developed effective treatments to resist the formation of amyloid protein in patients with Alzheimer’s disease and type 2 diabetes mellitus. Recently, scientists from the Technical University of Munich have found a solution by describing a new macrocyclic peptide molecule that can effectively inhibit the formation of amyloid proteins. The study was published in the international journal Angewandte Chemie International Edition.

• Diabetes: Natural peptides may improve glucose and insulin sensitivity and reduce body weight.

In a recent study published in the international journal Diabetes, researchers from the University of California found that obese mice were treated with peptides naturally found in the body called catechol somatostatin (CST). Or can significantly improve the level of glucose and insulin tolerance in mice, but also reduce the body weight of mice. The researchers point out that CST plays a key role in the recruitment and function of macrophages in the liver, as well as in regulating obesity-related liver inflammation and insulin tolerance.

• PLoS ONE: novel peptides can kill neuroma cells by blocking DNA replication.

Neurocytoma is one of the cancers that cause childhood death, accounting for 15% of childhood cancer deaths, and the 5-year survival time of high-risk neuroma patients is often 40% to 50%. Recently, in a research paper published in the international journal PLoS ONE, researchers found that a peptide called R9-caPep can target neuroma cells. It destroys the proliferation of nuclear antigen (PCNA) to kill neurocytoma cells. PCNA is an essential protein for DNA synthesis, replication and repair of neuroma cells.

• Immunity: A host defense peptide in frog mucus can kill many influenza virus strains.

Frog mucus contains molecules that kill bacteria and viruses, and scientists are beginning to study its use as a potential source of a new antimicrobial drug. In a new study, researchers from Emory University, Mount Sinai Icahn Medical School and the Rajiv-Gandhi Biotechnology Center in India reported that in Hydrophylax bahuvistara, a brightly colored tennis-sized frog species in southern India, A host defense peptide can eliminate a variety of influenza virus strains. The researchers named the newly identified peptide “urumin,” and the results are published in the journal Immunity.

In a new study, researchers from University College London, UK, reported a chemoselective, high-yield α-amino nitrile link. This α-amino nitrile connection only uses the molecules that may exist before the origin of life-hydrogen sulfide, thioacetate, ferricyanide or cyanoacetylene to produce α-peptides in water. The results of the study, entitled “Peptide ligation by chemoselective aminonitrile coupling in the water”, were published online in the journal Nature on July 10, 2019.

“Peptides are long chains of amino acids that are a key element of all life on Earth,” explained Professor Matthew Powner of University College London, who led the study, “they can further form proteins. In charge of the biological process. “Although scientists have clarified the relationship between amino acids, peptides, and proteins, a key question about the origin of life has never been solved: the synthesis of peptides from amino acids requires the involvement of enzymes; The enzyme that dominates this step is a protein; but to synthesize this protein, we need amino acids to synthesize peptides first. “This is a classic ‘chicken first or egg first’ question.” Professor Powner added.

Previously, many scientists have been studying how amino acids spontaneously form peptides. However, the conditions required for the reaction are extremely harsh and difficult to achieve. In the study, the team focused on aminonitriles, the precursor of amino acids. They found that these molecules are inherently reactive and can directly form peptides without first converting them into amino acids. In other words, the researchers have found a way to synthesize peptides without the need for amino acids.

α-amino nitrile coupling has high selectivity for α-amino nitrile coupling, so there is no need for the existence of the amino acids of these 20 proteins. Two basic characteristics make the peptide binding in water: the reactivity of α-amino nitrile and pK_aH make them connect under neutral pH. N-acylation keeps the peptide product produced by this connection stable and activates the peptide precursor, thus achieving biologically simulated N-C peptide binding.

This model unifies the synthesis of amino nitrile and biological α-peptide before the origin of life, and points out that the shorter N-acyl peptide nitrile is a potentially feasible substrate in the process of early evolution.

References

1. Canavelli, P., Islam, S., & Powner, M. W. (2019). Peptide ligation by chemoselective aminonitrile coupling in water. Nature.