Substrate Envelope Based Drug Design:
Synthesis and SAR Studies of HIV-1 Protease Inhibitors
We employ the substrate-envelope model to rationally design protease inhibitors against clinically relevant multidrug-resistant HIV-1 variants. Substrate-envelope model is a general structure-based strategy developed by the Schiffer laboratory that incorporates substrate envelope constraints into structure-based design. In collaboration with Bruce Tidor (MIT) and Tariq Rana (Sanford-Burnham) groups, we have successfully applied the substrate-envelope model to design several libraries of new HIV-1 protease inhibitors based on the (hydroxyethylamino)sulfonamide scaffold. (Ali, et.al., 2010, Nalam, et.al., 2010, Jorissen, et.al., 2009, Altman, et.al., 2008, Reddy, et.al., 2007, Chellappan, et.al., 2007, Ali, et.al., 2006)
The new inhibitors were synthesized and tested using high throughput enzymatic and antiviral assays. These collaborative efforts have led to the discovery of highly potent protease inhibitors that retain potency against clinically relevant multidrug-resistant protease variants. The Monogram Biosciences’ PhenoSenseTM assays demonstrated that these inhibitors were highly effective against a diverse panel of wild-type and drug-resistant viruses. Further development of these protease inhibitors may lead to more effective treatments against drug-resistant HIV-1.
Synthesis and SAR Studies of HCV NS3/4A Protease Inhibitors
We have applied the substrate envelope approach to decipher drug resistance against HCV NS3/4A protease inhibitors. We have discovered that, similar to HIV protease inhibitors, drug resistance against HCV NS3/4A inhibitors is defined by the balance of substrate recognition versus inhibitor binding. These findings have led to the development of a substrate envelope model for HCV NS3/4A protease, which we have used to understand the molecular basis of drug resistance against NS3/4A protease inhibitors. We are currently engaged in exploiting the HCV NS3/4A substrate envelope model to rationally design more robust protease inhibitors that are less susceptible to resistance.