Speaker: Md Taimuzzaman Sharif, MSCB student
Title: Development of Cyclic and Bicyclic Peptides Against the Main Protease (M^pro) of SARS-CoV-2
Abstract: Severe Acute Respiratory Syndrome (SARS-CoV-2) virus and its variants are responsible for Coronavirus disease 2019 (COVID-19) with more than seven million deaths since 2019. Main protease (M^pro) is one of the vital enzymes for the replication of SARS-CoV-2 and ultimate target for developing drugs. The inhibition of this viral enzyme effectively interrupts the formation of functional viral proteins required for the viral growth. Several small-molecule drugs are available against COVID-19. However, they often demonstrate lower target specificity, higher adverse effects and lead to resistance on prolong use. Peptide therapeutics, in contrast, are highly target specific and thus induce less toxic effect. However, they have some limitations such as flexible secondary structure, proteolytic instability, poor cell permeability and shorter half-life. Cyclization can reduce proteolytic instability, increase cell permeability and bioavailability. Previous studies from our group demonstrated that Temporin L like peptide (TLP) could effectively inhibit the main protease, however, this peptide showed a short half-life. In this study, four cyclic and four bicyclic peptides have been synthesized from three linear TLP analogues using hydrophobic linkers such as Hexafluorobenzene (C₆F₆), α, α’-Dibromo-P-Xylene and α, α’-Dichloro-P-Xylene. Moreover, bicyclic peptides have been synthesized using another two hydrophobic scaffolds such as 1,3,5-triacryloylhexahydro-1,3,5-triazinane (TATA) and 1,3,5-tris(bromomethyl)benzene (1,3,5-TBMB). All peptides have been characterized by mass spectrometry. Fluorescence resonance energy transfer (FRET) and selected ion monitoring (SIM) based LC-MS assays have been used to investigate the in-vitro inhibition efficiency of these analogues. Bicyclic peptides showed strong inhibition efficiency compared to their linear counterparts. Future studies will be directed to investigate gastric, intestinal, serum stability and cell viability of the best analogue.