Peptide Deformylase: A New Target in Antibacterial, Antimalarial and Anticancer Drug Discovery

Abstract

Peptide deformylase (PDF) is a class of metalloenzyme responsible for catalyzing the removal of the N-formyl group from N-terminal methionine following translation. PDF inhibitors are moving into new phase of drug development. Initially, PDF was considered as an important target in antibacterial drug discovery; however genome database searches have revealed PDF-like sequences in parasites (P. falciparum) and human, widening the utility of this target in antimalarial and anticancer drug discovery along with antibacterial. Using structural and mechanistic information together with high throughput screening, several types of chemical classes of PDF inhibitors with improved efficacy and specificity have been identified. Various drugs like, GSK-1322322 (Phase II), BB-83698 (Phase I), and LBM-415 (Phase I) have entered into clinical developments. Developments in the field have prompted us to review the current aspects of PDFs, especially their structures, different classes of PDF inhibitors, and molecular modeling studies. In nut shell, this review enlightens PDF as a versatile target along with its inhibitors and future perspectives of different PDF inhibitors.

Cellular Pharmacokinetics and Intracellular Activity of the Novel Peptide Deformylase Inhibitor GSK1322322 against Staphylococcus aureus Laboratory and Clinical Strains with Various Resistance Phenotypes: Studies with Human THP-1 Monocytes and J774 Murine Macrophages

“…This is observed even in infected cells where we see an almost complete dissociation between bacteria and the antibiotic. As the mode of action of GSK1322322 is that of a reversible binding to its bacterial target (55), we may propose that what the cell fractionation study reveals is the ability of the drug to freely diffuse into cells during the incubation but, thereafter, to be desorbed from it and be recovered in the supernatant of infected cells. The same proposal was made for fluoroquinolones, which also show no association with phagolysosomes after cell fractionation even though we know that they are very active against phagocytized bacteria (19,21).…”

Design and synthesis of 4′‐((5‐benzylidene‐2,4‐dioxothiazolidin‐3‐yl)methyl)biphenyl‐2‐carbonitrile analogs as bacterial peptide deformylase inhibitors

“…This crisis has resulted in an intensive research effort to develop a new class of compounds that exhibit novel mechanisms of antibacterial activity. Although microbial genomes have revealed an abundance of potentially useful targets, little has so far resulted from these much‐heralded efforts . Recent reports from several laboratories have suggested that peptide deformylase (PDF), an enzyme responsible for removing the N‐terminal of formyl group from newly synthesized polypeptides and may be suitable target for antibacterial drug discovery .…”

Bacterial Peptide deformylase inhibition of cyano substituted biaryl analogs: Synthesis, in vitro biological evaluation, molecular docking study and in silico ADME prediction

“…5 PDF has been a possible target that may fulfill all the criteria essential for good target to develop new antibacterial agents with novel mechanism of action. 6 The difference in protein synthesis between bacteria and mammalian cells stems from transformylation and deformylation of initiating methionine. The process for bacterial protein synthesis is initiated with N-formylmethionine, which is generated by transformylation of methionine.…”