Project 1: Structural Analysis of HIV Entry Inhibition Our overall objective is to provide an atomic-level understanding of opportunities for intervention in processes of cell entry by HIV. We plan to continue our structural studies on HIV gpl20 in the context of this program project on antagonism of HIV envelope function in cell entry. Our technical focus is on x-ray crystallography, so as to determine structures at sufficient resolution to develop mechanistic insights, but associated binding experiments and computations will also be performed.
Our aims i nclude using crystal structure to screen for new lead compounds, structural analyses of complexes of HIV gp120 with candidate inhibitory molecules, structural studies of HIV gpl20 interactions with other natural binding partners besides CD4, and innovative computational analyses of gp 120 plasticity. We build not only on our recent experience in this project, but also on our earlier structural investigations of CD4, HIV gp120s, and associated antibodies. We have adopted or developed both appropriate expression systems for making the required proteins and also appropriate assays for following inhibitory action. We interact with all other elements of the program project: most intimately with Project 3 on chemistry (Smith) and Project 5 on virology (Sodroski), but also significantly with Project 2 on peptidomimetics and miniproteins (Chaiken), Project 4 on thermodynamics (Freire), prospectively with Project 6 on dynamics by single-molecule FRET (Mothes), and importantly with the computation core (LaLonde).
|Ross, Patrick; Weihofen, Wilhelm; Siu, Fai et al. (2015) Isothermal chemical denaturation to determine binding affinity of small molecules to G-protein coupled receptors. Anal Biochem 473:41-5|
|Madani, Navid; Princiotto, Amy M; Schön, Arne et al. (2014) CD4-mimetic small molecules sensitize human immunodeficiency virus to vaccine-elicited antibodies. J Virol 88:6542-55|
|Herschhorn, Alon; Gu, Christopher; Espy, Nicole et al. (2014) A broad HIV-1 inhibitor blocks envelope glycoprotein transitions critical for entry. Nat Chem Biol 10:845-52|
|Kwon, Young Do; LaLonde, Judith M; Yang, Yongping et al. (2014) Crystal structures of HIV-1 gp120 envelope glycoprotein in complex with NBD analogues that target the CD4-binding site. PLoS One 9:e85940|
|Miura, Takuya; Hidaka, Koushi; Azai, Yukiko et al. (2014) Optimization of plasmepsin inhibitor by focusing on similar structural feature with chloroquine to avoid drug-resistant mechanism of Plasmodium falciparum. Bioorg Med Chem Lett 24:1698-701|
|Munro, James B; Mothes, Walther (2014) The HIV-1 Env trimer in HD. Structure 22:935-6|
|Emileh, Ali; Duffy, Caitlin; Holmes, Andrew P et al. (2014) Covalent conjugation of a peptide triazole to HIV-1 gp120 enables intramolecular binding site occupancy. Biochemistry 53:3403-14|
|Evans, Sean L; Schön, Arne; Gao, Qimeng et al. (2014) HIV-1 Vif N-terminal motif is required for recruitment of Cul5 to suppress APOBEC3. Retrovirology 11:4|
|Afanador, Gustavo A; Matthews, Krista A; Bartee, David et al. (2014) Redox-dependent lipoylation of mitochondrial proteins in Plasmodium falciparum. Mol Microbiol 94:156-71|
|Courter, Joel R; Madani, Navid; Sodroski, Joseph et al. (2014) Structure-based design, synthesis and validation of CD4-mimetic small molecule inhibitors of HIV-1 entry: conversion of a viral entry agonist to an antagonist. Acc Chem Res 47:1228-37|
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