Structural Basis of Resistance in Viral Drug Targets

HIV-1 Protease

HIV-1 protease cleaves viral polyproteins at specific sites to allow maturation and hence infectivity of the virus. Protease inhibitors are among small molecule antivirals used against HIV-1 infections. Understanding molecular interaction of HIV-1 protease with its peptide substrates and small molecule inhibitors is essential for drug resistance and drug design. In addition to acting as the scientific program manager of the Administration Core for a highly collaborative team led by Dr. Schiffer on HIV-1 protease, I have been collaborating with Dr. Rieko Ishima and leading specific projects on HIV-1 protease coevolution and drug resistance.

Exploiting the rich data and information on HIV-1 protease, we are developing new strategies such as incorporation of the substrate envelope constraint to drug design to counter drug resistance. These strategies have proven applicable to other targets including HCV protease (Kurt Yilmaz, N et al., Trends in Microbiology, Vol. 24, Iss. 7, pp. 547-557, 2017).

HCV NS3/4A Protease

Similar to HIV-1 protease, HCV NS3/4A protease cleaves diverse substrate sequences both within viral polyproteins and host cell proteins of the immune response. In addition to investigating resistance mechanisms and improving inhibitors accordingly, we are interested in the molecular reasons behind differential potency of inhibitors against different genotypes of HCV, and applying strategies from HCV to other flaviviral targets.