Our overall goal in this program project is to understand the potential of ligands of the human immunodeficiency virus (HIV-1) gp120 envelope glycoprotein to inhibit virus entry. HIV-1 infection is initiated by entry of the virus into host cells. The entry process depends on initial attachment of virus with host, and the molecular components of this attachment process are known. HIV-1 cell recognition occurs through envelope proteins on the viral spike, a heterotrimer of the gp120/gp41 complex. The interactions between gp120 and cell receptors appear to play the central role in viral entry. Hence, the design of antagonists of gp120 interactions with cell receptors is the central objective of the Program Project. We will utilize a comprehensive, interdisciplinary, multi-group approach that will combine chemical synthesis, high-resolution structure determination, thermodynamic and kinetic binding analyses, cell infection analyses, recombinant protein production and mutagenic analyses and computational modeling. We have already demonstrated our capacity to utilize this comprehensive approach as a team, and believe our experiences so far along with current starting points arrived at in our studies will successfully lead to important advances in mechanistic understanding and productive approaches to HIV-1 entry inhibitors. The Program Project will have 5 overarching specific aims. (1) Identify novel compounds that interact with functionally important regions of the HIV-1 gp120 glycoprotein. (2) Define the binding sites of the compounds on the gp120 glycoprotein. (3) Elucidate the mechanism of inhibition of HIV-1 entry associated with the compounds. (4) Optimize gp120-binding compounds for antiviral potency. (5) Understand the impact of variation in the HIV-1 envelope glycoproteins on the antiviral efficacy of the compounds. We will accomplish these aims through 5 Projects and 2 Cores. Project 1: Structure analysis of HIV-1 entry inhibition (Hendrickson);Project 2: Peptide-inspired competitive and allosteric inhibitors of HIV-1 entry (Chaiken);Project 3: Discovery and synthesis of small molecule CD4-gp120 antagonists (Smith);Project 4: Assembly and inhibition thermodynamics (Freire);Project 5: Structure-based antagonism of HIV-1 envelope function in cell entry (Sodroski);Core A: Computational modeling (LaLonde);Core B: Protein technologies (Chaiken). This program project will examine the potential of small molecules to inhibit HIV-1 viral entry and will identify candidate inhibitors as potential antagonists for AIDS prevention and treatment. Since many viral proteins involved in disease pathogenesis exhibit the type of plasticity found for HIV-1 gp120, we believe that the approaches we develop for the gp120 system will provide experimental paradigms for prevention and treatment of other diseases as well.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM056550-16
Application #
8130949
Study Section
Special Emphasis Panel (ZRG1-AARR-A (40))
Program Officer
Sakalian, Michael
Project Start
1997-08-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
16
Fiscal Year
2011
Total Cost
$1,687,060
Indirect Cost
Name
Drexel University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Castillo-Menendez, Luis R; Witt, Kristen; Espy, Nicole et al. (2018) Comparison of Uncleaved and Mature Human Immunodeficiency Virus Membrane Envelope Glycoprotein Trimers. J Virol 92:
Rashad, Adel A; Song, Li-Rui; Holmes, Andrew P et al. (2018) Bifunctional Chimera That Coordinately Targets Human Immunodeficiency Virus 1 Envelope gp120 and the Host-Cell CCR5 Coreceptor at the Virus-Cell Interface. J Med Chem 61:5020-5033
Moraca, Francesca; Rinaldo, David; Smith 3rd, Amos B et al. (2018) Specific Noncovalent Interactions Determine Optimal Structure of a Buried Ligand Moiety: QM/MM and Pure QM Modeling of Complexes of the Small-Molecule CD4 Mimetics and HIV-1 gp120. ChemMedChem 13:627-633
Castillo-Menendez, Luis R; Nguyen, Hanh T; Sodroski, Joseph (2018) Conformational Differences Between Functional Human Immunodeficiency Virus (HIV-1) Envelope Glycoprotein Trimers and Stabilized Soluble Trimers. J Virol :
Madani, Navid; Princiotto, Amy M; Mach, Linh et al. (2018) A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge. Nat Commun 9:2363
Kisalu, Neville K; Idris, Azza H; Weidle, Connor et al. (2018) A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite. Nat Med 24:408-416
Parajuli, Bibek; Acharya, Kriti; Bach, Harry C et al. (2018) Restricted HIV-1 Env glycan engagement by lectin-reengineered DAVEI protein chimera is sufficient for lytic inactivation of the virus. Biochem J 475:931-957
Ma, Xiaochu; Lu, Maolin; Gorman, Jason et al. (2018) HIV-1 Env trimer opens through an asymmetric intermediate in which individual protomers adopt distinct conformations. Elife 7:
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
Espy, Nicole; Pacheco, Beatriz; Sodroski, Joseph (2017) Adaptation of HIV-1 to cells with low expression of the CCR5 coreceptor. Virology 508:90-107

Showing the most recent 10 out of 146 publications