Abstract
HIV-1 gp120 undergoes multiple conformational changes both before and after binding to the host CD4 receptor. BMS-626529 is an attachment inhibitor (AI) in clinical development (administered as prodrug BMS-663068) that binds to HIV-1 gp120. To investigate the mechanism of action of this new class of antiretroviral compounds, we constructed homology models of unliganded HIV-1 gp120 (UNLIG), a pre-CD4 binding-intermediate conformation (pCD4), a CD4 bound-intermediate conformation (bCD4), and a CD4/co-receptor-bound gp120 (LIG) from a series of partial structures. We also describe a simple pathway illustrating the transition between these four states. Guided by the positions of BMS-626529 resistance substitutions and structure–activity relationship data for the AI series, putative binding sites for BMS-626529 were identified, supported by biochemical and biophysical data. BMS-626529 was docked into the UNLIG model and molecular dynamics simulations were used to demonstrate the thermodynamic stability of the different gp120 UNLIG/BMS-626529 models. We propose that BMS-626529 binds to the UNLIG conformation of gp120 within the structurally conserved outer domain, under the antiparallel β20–β21 sheet, and adjacent to the CD4 binding loop. Through this binding mode, BMS-626529 can inhibit both CD4-induced and CD4-independent formation of the “open state” four-stranded gp120 bridging sheet, and the subsequent formation and exposure of the chemokine co-receptor binding site. This unique mechanism of action prevents the initial interaction of HIV-1 with the host CD4+ T cell, and subsequent HIV-1 binding and entry. Our findings clarify the novel mechanism of BMS-626529, supporting its ongoing clinical development. Proteins 2015; 83:331–350. © 2014 Wiley Periodicals, Inc.
Highlights
Antiretroviral drugs used to treat human immunodeficiency virus type 1 (HIV-1) infection can target several distinct steps within the viral lifecycle
As the gp120–CD4 interaction represents the first step in CD4-dependent HIV-1 cell entry, the conserved CD4 binding site provides an attractive target for new antiretroviral agents
In the unliganded HIV-1 gp120 (UNLIG) model (Fig. 1a), the V1/V2, V3 and bridging domain are in a nonCD4-binding conformations and there is a large hydrophobic cavity under the bridging domain and within the outer domain
Summary
Antiretroviral drugs used to treat human immunodeficiency virus type 1 (HIV-1) infection can target several distinct steps within the viral lifecycle. The interaction of gp[120] with CD4 stabilizes[7,12,13] changes in the b21–b20 sheet conformation that leads to “opening” of the trimer spike and re-ordering of the bridging sheet (b3– b2-b21–b20) This directs the V1/V2 loops toward CD4 and away from V3 to form and expose the co-receptor binding site.[11] As the gp120–CD4 interaction represents the first step in CD4-dependent HIV-1 cell entry, the conserved CD4 binding site provides an attractive target for new antiretroviral agents. There are no approved agents that target this initial gp120–CD4 interaction
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
