This Program Project on """"""""Structure-Based Antagonism of HlV-1 Envelope Function in Cell Entry"""""""" will lead to a new understanding of the HlV-1 envelope (Env) structure and structural transitions that accompany cell entry, that in turn will permit the development of potent, selective antagonists of HIV-1 entry for both intervention and prevention of the AIDS pandemic. The major focus of the Synthetic Thrust (Project 3) within this Program Project will be the development of new small molecule antagonists of the CD4-gp120 protein-protein interaction that mediate viral entry into target host cells. The CD4 binding site of gp120 has great promise as a major therapeutic target site on the Env protein for inhibitor design, given the well-defined binding surface that is highly conserved in diverse virus sub-types. Ligand binding at this site, however, has also evolved to trigger the allosteric activation process that the virus employs to mediate fusion. As we proceed forward, we will build upon our recent discovery of DMJ-ll-121, a small molecule that targets two highly conserved sites of gp120 and in turn neutralizes HlV-1 without triggering the allosteric response in gp120. The guidelines developed during the design of DMJ-ll-121 provide a roadmap for the discovery of new small molecule inhibitors of the dynamic protein-protein interactions. This roadmap will also be employed to optimize new leads identified by the screening programs within the Program Project. The Synthetic Thrust, in conjunction with the other Projects will also prepare conjugates of the antagonists with molecular probes to study structurally the biochemical mechanisms associated with HlV-1 neutralization. Photoaffinity labels will be attached covalently to highly active antagonists to elucidate the binding sites of inhibitors that entrap the Env in an inactive conformation. The dynamic processes associated with small molecule binding to the HIV-1 Env trimer will also be interrogated with recently developed single molecule FRET probes. Finally, innovative covalent labeling strategies to append a tetrairidium cluster to validated antagonists will facilitate binding site analysis within solubilized Env trimers by SP-cryoEM.

Public Health Relevance

Inhibition of the HIV entry process has been validated as a successful strategy for AIDS chemotherapy. Currently approved inhibitors however are not widely accessible due to production and cost limitations. Recent studies by this Program Project have demonstrated that small molecule viral entry inhibitors targeting well conserved sites of gp120 can lead to highly selective full antagonists that can neutralize a wide breadth of viral isolates. Efforts to discover and develop new more potent entry inhibitors based on small molecules thus hold the promise of providing clinically relevant therapeutics for both the treatment and prevention of HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM056550-18
Application #
8740489
Study Section
Special Emphasis Panel (ZRG1-AARR-E)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
18
Fiscal Year
2014
Total Cost
$310,010
Indirect Cost
$111,810
Name
Drexel University
Department
Type
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Espy, Nicole; Pacheco, Beatriz; Sodroski, Joseph (2017) Adaptation of HIV-1 to cells with low expression of the CCR5 coreceptor. Virology 508:90-107
Nguyen, Hanh T; Madani, Navid; Ding, Haitao et al. (2017) Evaluation of the contribution of the transmembrane region to the ectodomain conformation of the human immunodeficiency virus (HIV-1) envelope glycoprotein. Virol J 14:33
Afanador, Gustavo A; Guerra, Alfredo J; Swift, Russell P et al. (2017) A novel lipoate attachment enzyme is shared by Plasmodium and Chlamydia species. Mol Microbiol 106:439-451
Witt, Kristen C; Castillo-Menendez, Luis; Ding, Haitao et al. (2017) Antigenic characterization of the human immunodeficiency virus (HIV-1) envelope glycoprotein precursor incorporated into nanodiscs. PLoS One 12:e0170672
Acharya, Kriti; Rashad, Adel A; Moraca, Francesca et al. (2017) Recognition of HIV-inactivating peptide triazoles by the recombinant soluble Env trimer, BG505 SOSIP.664. Proteins 85:843-851
Pancera, Marie; Lai, Yen-Ting; Bylund, Tatsiana et al. (2017) Crystal structures of trimeric HIV envelope with entry inhibitors BMS-378806 and BMS-626529. Nat Chem Biol 13:1115-1122
Prévost, Jérémie; Zoubchenok, Daria; Richard, Jonathan et al. (2017) Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses. J Virol 91:
Pacheco, Beatriz; Alsahafi, Nirmin; Debbeche, Olfa et al. (2017) Residues in the gp41 Ectodomain Regulate HIV-1 Envelope Glycoprotein Conformational Transitions Induced by gp120-Directed Inhibitors. J Virol 91:
Herschhorn, Alon; Sodroski, Joseph (2017) An entry-competent intermediate state of the HIV-1 envelope glycoproteins. Receptors Clin Investig 4:
Ding, Shilei; Verly, Myriam M; Princiotto, Amy et al. (2017) Short Communication: Small-Molecule CD4 Mimetics Sensitize HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity by Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Nonhuman Primates. AIDS Res Hum Retroviruses 33:428-431

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