<\/p>\n

The peptide deformylase (PDF) is a unique feature of prokaryotes and believed not to exist in eukaryotes up to even only\u00a0a few years ago. PDF is essential for ribosomal protein\u00a0translation by deformylating the initiating N-formylmethionine\u00a0in prokaryotes. Since the initiating methionine of eukaryotes is\u00a0not N-formylated, PDF inhibitors were considered as a possible\u00a0antibacterial drug target. Many researchers have studied PDF\u00a0and PDF inhibitors to overcome the drug resistance problem.\u00a0Currently, there are 280 papers on the structure and function of\u00a0bacterial PDF, and 103 papers on bacterial PDF inhibitors.\u00a0Among them, LBM415 and BB-83698 are already under\u00a0clinical study as novel antibiotics candidates.<\/p>\n

However, PDF also exists in the mitochondria of eukaryotes including humans, and is crucial for cell growth according to recent papers. The first eukaryotic PDF was\u00a0reported to be in the mitochondria and plastids of Arabidopsis\u00a0thaliana. A bioinformatics study found many PDF-like\u00a0genes in parasites, plants, and mammals. In 2004, Lee and coworkers reported that non-peptidyl bacterial PDF inhibitor\u00a0actinonin suppresses the proliferation of cancer cells more\u00a0than normal cells through a tumor-specific mitochondrial\u00a0membrane depolarization and ATP depletion mechanism by\u00a0interacting with HsPDF. It also could remove the N-formyl\u00a0capping of model human mitochondrial peptides in prokaryotes. However, the function of HsPDF in vivo was unclear.\u00a0The crystal structure of HsPDF was determined by EscobarAlvarez et al. and the mechanism of action was proposed. It\u00a0is known that HsPDF processes formylated peptides derived\u00a0from mitochondrial DNA-encoded proteins by a Co^{2+<\/sup>\u00a0dependent manner. The bacterial PDF and HsPDF have both\u00a0similarities and differences in their structures. The complex\u00a0structure of HsPDF and actinonin, a naturally occurring\u00a0inhibitor derived from the Streptomyces species, shows an\u00a0overall structural similarity to the complex structure of bacterial PDF and actinonin, but they have structural differences\u00a0at the C-terminus.<\/p>\n}

In the previous study, we made novel bacterial PDF inhibitors, PMT analogs, which named after ProMediTech Ltd.\u00a0In the progress of developing PMT analogs, we discovered\u00a0about 600 kinds of compounds in our library. PMT analogs\u00a0have potent antibacterial activity against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. These bacteria were known to cause respiratory tractassociated infections. Structural modification of PMT analogs\u00a0makes these compounds more effective especially against\u00a0Staphylococcus aureus. PMT analogs have a peptidomimetic structure like actinonin, but have stronger activity and\u00a0better pharmacokinetic properties than actinonin.<\/p>\n

Based on our previous studies, we predicted that PMT\u00a0analogs could bind to HsPDF and inhibit the proliferation of\u00a0cancer cells like actinonin. In order to prove our hypothesis,\u00a0we carried out virtual screening of PMT analogs with GOLD\u00a0software and DOCK6.5 from UCSF and selected\u00a043 compounds from our library. The MTT assay was\u00a0performed to test the antitumor activity for 10 highly scored\u00a0compounds out of the 43 compounds. Among the 10 compounds, 4 analogs, PMT-172, PMT-173, PMT-199, and PMT-201, showed similar or better activity compared to actinonin.\u00a0We prepared a HsPDF construct that has an enhanced\u00a0expression level by codon optimization in E. coli. Then,\u00a0^{1<\/sup>H-CPMG-T2 filter NMR experiments were performed\u00a0with purified protein, and it was confirmed that PMT-172 and\u00a0PMT-199 could bind directly to HsPDF. The docking models\u00a0between PMT-172, PMT-199 and HsPDF from the X-ray\u00a0crystal structure (PDB 3G5K) with DOCK6.5 were obtained.\u00a0It was identified that PMT-172 and PMT-199 have an N-alkyl\u00a0amide and sulfonyl amide group, respectively, at the functional group R3<\/sup>\u00a0and R4<\/sup>.\u00a0Understanding the structural characteristics of PMT-172 and\u00a0PMT-199 might yield clues to design novel anticancer drug\u00a0candidates that have better physical properties and binding\u00a0affinities through modification of the functional groups.<\/p>\n}

 <\/p>\n

Reference:<\/p>\n

Kim, Won-Je, et al. “Bacterial peptide deformylase inhibitor PMT analogs inhibit cancer cell growth by interacting with human peptide deformylase.”\u00a0Chinese science bulletin<\/i><\/em>\u00a059.32 (2014): 4274-4282.<\/p>\n

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