HIV-1 Protease Inhibitors

We use structure-based drug design (SBDD), combined with the substrate envelope model and extensive structure-activity relationship studies, to develop novel HIV-1 protease inhibitors with improved antiviral potency and resistance profile. We closely work with Dr. Celia Schiffer and her team to elucidate the molecular mechanisms of drug resistance and develop SBDD strategies to rationally design viral protease inhibitors with improved activity against drug-resistant variants. Using the substrate envelope model, we designed highly potent HIV-1 protease inhibitors, displaying exceptional antiviral potencies against a panel of clinically relevant multidrug-resistant HIV-1 strains. More recently, we explored HIV-1 protease inhibitors incorporating stereochemically defined moieties designed to optimize hydrogen bonding and van der Waals interactions in the substrate envelope. These inhibitors showed excellent antiviral activities against highly drug-resistant HIV-1 strains. We continue to explore novel HIV-1 protease inhibitors with diverse modifications to identify optimal combination of modifications, with the aim of developing inhibitors with improved potency and a higher barrier to resistance.

Relevant Publications:

Lockbaum, G. J.; Rusere, L. N.; Henes, M.; Kosovrasti, K.; NageshwaraRao, D.; Lee, S-K.; Spielvogel, E.; Nalivaika, E. A.; Swanstrom, R.; Yilmaz, N. K.; Schiffer, C. A.; Ali, A. HIV-1 Protease Inhibitors with a P1 Phosphonate Modification Maintain Potency against Drug-Resistant Variants by Increased Interactions with Flap Residues. J. Med. Chem. 2023, 257, 115501.

Rusere, L. N.; Lockbaum, G. J.; Lee, S-K.; Henes, M.; Kosovrasti, K.; Spielvogel, E.; Nalivaika, E. A.; Swanstrom, R.; Yilmaz, N. K.; Schiffer, C. A.; Ali, A. HIV-1 Protease Inhibitors Incorporating Stereochemically Defined P2’ Ligands To Optimize Hydrogen Bonding in the Substrate Envelope. Med. Chem. 2019, 62, 8062–8079.