Therapeutic application of PPE2 protein of Mycobacterium tuberculosis in inhibiting tissue inflammation

Abstract There is an increasing need to develop biological anti‐inflammatory agents that are more targeted, effective, and with lesser side effects as compared to conventional chemical drugs. In the present study, we found that Mycobacterium tuberculosis protein PPE2 and a synthetic derivative peptide can suppress the mast cell population and inhibit several vasoactive and fibrogenic mediators and pro‐inflammatory cytokines induced by mast cells in formalin‐induced tissue injury. PPE2 was found to inhibit transcription from the promoter of stem cell factor, important for mast cell maintenance and migration. Thus, PPE2/peptide can be used as a potent nonsteroidal therapeutic agent for the treatment of inflammation and tissue injury

Multiple e‑Pharmacophore Modeling, 3D-QSAR, and High-Throughput Virtual Screening of Hepatitis C Virus NS5B Polymerase Inhibitors

The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRP) is a crucial and unique component of the HCV RNA replication machinery and a validated target for drug discovery. Multiple crystal structures of NS5B inhibitor complexes have facilitated the identification of novel compound scaffolds through in silico analysis. With the goal of discovering new NS5B inhibitor leads, HCV NS5B crystal structures bound with inhibitors in the palm and thumb allosteric pockets in combination with ligands with known inhibitory potential were explored for a comparative pharmacophore analyses. The energy-based and 3D-QSAR-based pharmacophore models were validated using enrichment analysis, and the six models thus developed were employed for high-throughput virtual screening and docking to identify nonpeptidic leads. The hits derived at each stage were analyzed for diversity based on the six pharmacophore models, followed by molecular docking and filtering based on their interaction with amino acids in the NS5B allosteric pocket and 3D-QSAR predictions. The resulting 10 hits displaying diverse scaffold were then screened employing biochemical and cell-based NS5B and anti-HCV inhibition assays. Of these, two molecules H-5 and H-6 were the most promising, exhibiting IC₅₀ values of 28.8 and 47.3 μM against NS5B polymerase and anti-HCV inhibition of 96% and 86% at 50 μM, respectively. The identified leads comprised of benzimidazole (H-5) and pyridine (H-6) scaffolds thus constitute prototypical molecules for further optimization and development as NS5B inhibitors