6p9n

Publication Abstract from PubMed

The HIV-1 envelope glycoprotein (Env) trimer mediates virus entry into cells. The "closed" conformation of Env is resistant to non-neutralizing antibodies (nnAbs). These antibodies mostly recognize occluded epitopes that can be exposed upon binding of CD4 or small-molecule CD4 mimetics (CD4mc). Here, we describe a new family of small molecules that expose Env to nnAbs and sensitize infected cells to antibody-dependent cellular cytotoxicity (ADCC). These compounds have limited capacity to inhibit virus infection directly, but are able to sensitize viral particles to neutralization by otherwise non-neutralizing antibodies. Structural analysis shows that some analogs of this family of CD4mc engage the gp120 Phe43 cavity by contacting the highly-conserved D368 residue, making them attractive scaffolds for drug development.IMPORTANCE HIV-1 has evolved multiple strategies to avoid humoral responses. One efficient mechanism is to keep its envelope glycoproteins (Env) in its "closed" conformation. Here we report on a new family of small molecules able to "open-up" Env, thus exposing vulnerable epitopes. This new family of molecules bind in the Phe43 cavity and contact the highly-conserved D368 residue. The structural and biological attributes of this family of molecules make them good candidates for drug development.

A new family of small-molecule CD4-mimetic compounds contact the highly conserved aspartic acid 368 of HIV-1 gp120 and mediates ADCC.,Ding S, Grenier MC, Tolbert WD, Vezina D, Sherburn R, Richard J, Prevost J, Chapleau JP, Gendron-Lepage G, Medjahed H, Abrams C, Sodroski J, Pazgier M, Smith AB 3rd, Finzi A J Virol. 2019 Sep 25. pii: JVI.01325-19. doi: 10.1128/JVI.01325-19. PMID:31554684^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.