Venom peptides as inhibitory agents against flaviviral proteases
Cai, Maggie Weiling
Date of Issue2011
School of Biological Sciences
DUKE-NUS Graduate Medical School Singapore
Due to the lack of vaccines and effective therapies, infectious diseases caused by members of the Flaviviridae family pose a major healthcare concern worldwide. The nonstructural protein 3(NS3) is multifunctional, with serine protease activity in its N-terminal domain, RNA triphosphatase and helicase activity in its C-terminal domain. With its pivotal roles in flavivirus replication, i.e. viral polyprotein processing and RNA replication, NS3 is an attractive target for antiviral therapeutics development. Previously, venom secreted phospholipase A2 (sPLA2) has been implicated with potential anti-human immunodeficiency virus (HIV) activity. Hence to evaluate the potential inhibitory actions of nine synthetic peptides, designed based on snake venom sPLA2, four experimental approaches, namely, in vitro biochemical protease assays, in vivo cell-based assays, biophysical surface plasmon resonance and protein crystallization, were employed in this study. All nine peptides exhibit good inhibition against flaviviral proteases in biochemical assays. For in vivo studies, low degree of inhibition was observed in peptides treated cells. This was however expected, probably due to limited cellular entry resulting from the large size and highly hydrophilic nature of the peptides. Importantly, these peptides exert no cytotoxicity up to at least 30μM. Although shown to have limited inhibitory actions against flaviviral proteases in vivo, it is important that these peptides exert no cytotoxicity, hence suggesting for the potential of these peptides to emerge as the next-generation antiviral therapeutics.
Final Year Project (FYP)
Nanyang Technological University