Human immunodeficiency virus (HlV-1) is the etiologic agent of acquired immunodeficiency syndrome (AIDS). The global HIV-1 pandemic (~35 million people infected) is sustained by 2-S million new infections annually. Changing the course of this pandemic requires prevention of HlV-1 transmission, most of which occurs sexually. In the absence of an effective vaccine, the use of specific antiretroviral drugs has been investigated and shown to protect, in a partial manner, at-risk sex partners from HIV-1 infection. However, partial efficacy, drug side effects, suboptimal compliance and the emergence of drug-resistant viruses limit the general applicability of these agents as prophylactic measures. New broadly active antiviral agents that can be used as topical microbicides hold the promise of addressing these deficiencies. The HlV-1 envelope glycoproteins (Envs), which mediate virus entry into target cells, represent attractive targets for such prophylactic agents. The HIV-1 Envs are exposed on the viral surface, are accessible to water-soluble inhibitors and are present in low numbers on each virion. Env inhibitors used as microbicides need not be systemically absorbed or taken up by host cells, limiting potential toxicity. Conserved elements of Env mediate receptor binding, conformational changes, and membrane fusion, providing several potential targets for inhibition. Although some HIV-1 entry inhibitors have been identified, drug-resistant HlV-1 variants either exist naturally or develop during treatment. To identify new broad-range inhibitors of HIV-1 entry, we have developed and utilized an Env-dependent cell-cell fusion screening assay. To date, the primary screen has been conducted on more than 600,000 compounds. The hits from the primary screen are in the process of being confirmed and validated, and two novel HlV-1 Env inhibitors have been identified recently. In this project, specific and broad range inhibitors, including analogues modified to improve potency while retaining breadth, will be characterized. We will also identify the target protein, the mechanism of inhibition of HIV-1 entry, and the binding site ofthe inhibitor. The proposed studies should permit us to classify inhibitors into groups;synergy or antagonism among the groups will also be explored. The inhibitors will serve as novel probes to understand the complex, multi-step process of HIV-1 entry, and could represent leads for prophylactic microbicides and treatments for already infected individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM056550-18
Application #
8740491
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
$346,850
Indirect Cost
$148,650
Name
Drexel University
Department
Type
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:
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
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

Showing the most recent 10 out of 146 publications