Dengue virus (DENV) NS2B/NS3pro protease is a non-structural dengue protease that plays a pivotal role in viral maturation and has been identified as a viable drug target for treating dengue viral infections. Currently, there is no vaccine or antiviral drug available to treat these infections which are fatal in a small number of cases and debilitating in a majority of cases. A substrate-based peptide aldehyde inhibitor (PhAc-Lys-Arg-Arg-CHO) targeting DENV3 NS2B/NS3pro protease has been reported [1], with a moderate inhibitory activity (IC50 = 10 �M). Analogues of this compound are three orders of magnitude more potent inhibitors of the corresponding West Nile Virus NS2B/NS3pro enzyme [2]. The hydrophilic nature of this highly charged peptide leads to low cell-permeability, rendering it undesirable as a drug candidate.We present some approaches to generating potent, selective and more drug-like DENV NS2B/NS3pro inhibitors evaluated in in vitro enzymatic assay. Selected compounds and their activities will be described and discussed.References1. Schuller, A., Yin, Z., Chia, C.S., Doan, D., Kim, H. K., Shang, L., Loh, T. P., Hill, J., Vasudevan, S. G. 2011, 92(1), pp 96-1012. Stoermer, M., Chappell, K., Liebcher, S., Jensen, C., Gan, Chun., Gupta, P., Xu, W. J., Young, P., Fairlie, D. J. Med. Chem. 2008, 51(18), pp 5714-5721

Novel inhibitors of DENV NS2B/NS3pro protease

246th National Meeting (2013)

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