Novel Peptide Drugs to Treat Multiple Diseases (Part Two)

2017-09-28

5. Synthetic Peptides Targeting CD36 Attenuate Lipopolysaccharide-Induced Inflammation

Synthetic amphipathic helical peptides (SAHPs) designed as apolipoprotein A-I mimetics are known to bind to class B scavenger receptors (SR-Bs), SR-BI, SR-BII, and CD36, receptors that mediate lipid transport and facilitate pathogen recognition. In this study, the author evaluated SAHPs, selected for targeting human CD36, by their ability to attenuate LPS-induced inflammation, endothelial barrier dysfunction, and acute lung injury (ALI). L37pA, which targets CD36 and SR-BI equally, inhibited LPS-induced IL-8 secretion and barrier dysfunction in cultured endothelial cells while reducing lung neutrophil infiltration by 40% in a mouse model of LPS-induced ALI. A panel of 20 SAHPs was tested in HEK293 cell lines stably transfected with various SR-Bs to identify SAHPs with preferential selectivity toward CD36. Among several SAHPs targeting both SR-BI/BII and CD36 receptors, ELK-B acted predominantly through CD36. Compared with L37pA, 5A, and ELK SAHPs, ELK-B was most effective in reducing the pulmonary barrier dysfunction, neutrophil migration into the lung, and lung inflammation induced by LPS. We conclude that SAHPs with relative selectivity toward CD36 are more potent at inhibiting acute pulmonary inflammation and dysfunction. These data indicate that therapeutic strategies using SAHPs targeting CD36, but not necessarily mimicking all apolipoprotein A-I functions, may be considered a possible new treatment approach for inflammation-induced ALI and pulmonary edema.

6. Minihepcidin Peptides Maybe a Choice for the Treatment of β-Thalassemia and Polycythemia Vera

In β-thalassemia and polycythemia vera (PV), disordered erythropoiesis triggers severe pathophysiological manifestations. β-Thalassemia is characterized by ineffective erythropoiesis, reduced production of erythrocytes, anemia, and iron overload and PV by erythrocytosis and thrombosis. Minihepcidins are hepcidin agonists that have been previously shown to prevent iron overload in murine models of hemochromatosis and induce iron-restricted erythropoiesis at higher doses.

In conclusion, the drug-like minihepcidin peptides offer a new potential pharmacotherapeutic approach to achieve therapeutic iron restriction in the treatment of β-thalassemia, polycythemia vera (PV), and perhaps other less common disorders associated with abnormal erythropoiesis.

7. New Target Identified for Reducing Cancer Metastasis

Scientists report that a protein is constantly expressed by cancer cells and quiescent in healthy ones appears to be a solid target for reducing cancer's ability to spread. The WASF3 protein enables cancer cell invasion and helps WASF3 keep its form and function by interrupting its relationship with another protein. The team first suspected WASF3's role in metastasis in 2002 when they first identified the gene in a child with neuroblastoma. They knocked the gene out a decade ago and saw it stopped cancer spread. Then they used mass spectroscopy to discover the proteins WASF3 interacts with and found CYFIP1 high on the list. Now the team worked with another person to develop stapled peptides that essentially disconnect WASF3 from its stabilizing force CYFIP1. There is already one clinical trial underway for a peptide that interrupts the interaction between two other proteins. So the therapeutic pendulum is swinging toward these peptides.

8. Promising peptide for TBI, heart attack and stroke

Strokes, heart attacks and traumatic brain injuries are separate diseases with certain shared pathologies. These diseases achieve a common end that cell death and human injury due to hypoxia or lack of oxygen. In these diseases, a lack of blood supply to affected tissues begins a signaling pathway that ultimately halts the production of energy-releasing ATP molecules. By employing derivatives of humanin, a naturally occurring peptide encoded in the genome of cellular mitochondria, researchers are working to interrupt this process for buying precious time for tissues whose cellular mechanisms have called it quits.

The present findings could provide a new lead compound for the development of drug therapies for necrosis-related diseases. The humanin derivatives work by counteracting the decrease in ATP levels caused by necrosis. The researchers tested the effectiveness of the humanin analogues AGA(C8R)-HNG17 and AGA-HNG by treating neuronal cells with these peptides prior to exposure to a necrotic agent. The experiments were a success.

9. Almac Discovery is Granted Orphan Drug Designation for ALM201 Programme in Ovarian Cancer

ALM201 is a first-in-class therapeutic peptide developed to mimic some of the properties of the naturally occurring protein FKBPL. The development of ALM201 by Almac Discovery builds upon initial research work by Professor Tracy Robson who has shown that FKBPL is a naturally secreted protein with effects on a number of important tumour biology processes including cancer stem cells and angiogenesis. Recently, the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to drug candidate ALM201 in the treatment of ovarian cancer.

10. Fish Peptide can Effectively Treat Cardiovascular Disease

Urotensin II (UII) is a cyclic neuropeptide that was first isolated from the urophysis of teleost fish on the basis of its ability to contract the hindgut. UII activates a G protein-coupled receptor called UT to modulate a number of signalling pathways including intracellular Calcium. Interestingly, the peptide can constrict some blood vessels yet dilate others. The review has shown that UII can modulate a vast array of biologic activities encompassing the cardiovascular system, kidneys and central nervous system.

References:

Bocharov, A. V., Wu, T., Baranova, I. N., Birukova, A. A., Sviridov, D., Vishnyakova, T. G., ... & Birukov, K. G. (2016). Synthetic amphipathic helical peptides targeting cd36 attenuate lipopolysaccharide-induced inflammation and acute lung injury. The Journal of Immunology, 197(2), 611-619.

Casu, C., Oikonomidou, P. R., Chen, H., Nandi, V., Ginzburg, Y., Prasad, P., ... & Ganz, T. (2016). Minihepcidin peptides as disease modifiers in mice affected by β-thalassemia and polycythemia vera. Blood, 128(2), 265-276.

Teng, Y., Bahassan, A., Dong, D., Hanold, L. E., Ren, X., Kennedy, E. J., & Cowell, J. K. (2016). Targeting the WASF3-CYFIP1 complex using stapled peptides suppresses cancer cell invasion. Cancer research, 76(4), 965-973

Vaudry, H., Leprince, J., Chatenet, D., Fournier, A., Lambert, D. G., Le Mével, J. C., ... & Vaudry, D. (2015). International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, Urotensin II-Related Peptide, and Their Receptor: From Structure to Function. Pharmacological reviews, 67(1), 214-258.

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