Friday, April 25, 2025
4/25/2025
Design of inhibitors targeted to the CD4 binding site on HIV - 1gp120 - Project Summary/Abstract The HIV-1 envelope glycoprotein (Env) gp120 is critical in mediating viral entry into host cells and is a prime target for small-molecule drug and vaccine development. The recent FDA approval of the Env gp120–targeting fostemsavir (Rukobia, ViiV Healthcare) validates this protein as a target for drug development. However, a 48- week Phase 2b clinical trial reported several resistant mutants that reduced susceptibility to fostemsavir. Therefore, a critical need exists for the continued development of novel drugs against this target for effective therapies. Our group has made significant advances toward meeting this urgent need by developing a new class of HIV-1 entry inhibitors targeting the Phe43 cavity of HIV-1 Env gp120, distinct from the fostemsavir binding site. In addition, we discovered that some of the most active gp120 antagonists are also active against HIV-1 reverse transcriptase (RT). However, because the Phe43 cavity is very narrow and cannot accommodate any larger scaffolds, we hypothesize that modifications to increase the RT-inhibitory activity would result in a loss of gp120-targeted entry inhibitory activity and vice versa. Based on these considerations, we decided to focus on optimizing the gp120-antagonistic activity in the current proposal. We gained extensive knowledge of the 3D structural features from resolving the crystal structures of gp120–antagonist complexes. We also identified critical 2D structural fingerprints in the inhibitors that made them strong gp120 antagonists with weak RT inhibitory activity. We hypothesize that these novel findings from structural analyses will help to dissect the mechanism of these inhibitors and pave the way to design and optimize lead compounds to a novel class of entry inhibitors targeting specifically the Phe43 cavity of gp120. We aim to develop 2–3 HIV-1 entry inhibitors as potential preclinical and clinical candidates. This well-coordinated proposal is expected to generate highly potent, clinically relevant, orally available drugs as HIV-1 entry inhibitors and effective against resistant mutants. In addition, these novel entry inhibitors are expected to enrich the availability of drugs that prevent virus entry by targeting gp120 and serve as a new arsenal for combination therapies, especially in treatment-experienced patients, contributing to the formulation of long-acting drugs.
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