The overarching goal of Project 2 within this multidisciplinary POI Program Project is the development of HIV- 1 entry inhibitors that target the Env spike before the virus encounters the host cell by employing peptide and protein science strategies to design viral entry antagonists. In addition, the derived peptide antagonists, as well as the peptidomimetics emerging from the parent peptides, will be utilized as mechanistic probes to define the vulnerabilities ofthe HlV-1 Env complex to deactivation. Recently, we have discovered a family of peptide triazoles that target a conserved footprint, on gp 120, which overlaps significantly with the CD4 binding site. These inhibitors bind gp120 with nanomolar affinity and block interactions at the sites responsible for binding with both of the cellular receptors required for viral entry. A combination of sequence minimization, non-natural amino acid substitutions, nuclear magnetic resonance and computational simulations have revealed a core pharmacophore in the peptide triazoles that consists of three amino acid residues. Biophysical and functional studies suggest that the inhibitors stabilize a partially structured state of gp 120 and, through an allosteric mechanism, disrupt the conformational transitions of Env complex required to mediate viral entry. In addition, we recently discovered that peptide triazoles, likely by conformational effects, cause gp 120 shedding in the absence of host cells and consequent irreversible inactivation of virus. Further, and of considerable interest, peptide triazole variants containing a free sulfiiydryl group disrupt the structural integrity of HIV-1 envelope membrane, leading to leakage of the intra-viral capsid protein p24. Going forward, these results will be employed to design and validate peptidomimetic and small molecule Env antagonists that inactivate virus. To achieve the overall goals of this Program Project, three Specific Aims will be pursued by Project 2: [1] design, synthesize and develop structure-simplified peptide and peptidomimetic antagonists of HIV-1 envelope and host cell receptor interactions;[2] map the gpl20 binding site for the peptide and peptidomimetic antagonists that define the conformational transitions of gp 120 triggered by peptide triazoles;and [3] determine the mechanistic effects of peptide triazole and peptidomimetic inhibitors on Env protein and virus particle structure and function, and from this understanding, delineate vulnerabilities of the virus Env to antagonism and inactivation. The peptide-based antagonists developed by Project 2 will contribute substantially to the overall effort of this Program Project to understand structural mechanisms of the Env protein entry machine, which in turn holds the promise of providing new tactics for both AIDS prevention and intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM056550-18
Application #
8740488
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
$301,523
Indirect Cost
$105,241
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:
Madani, Navid; Princiotto, Amy M; Zhao, Connie et al. (2017) Activation and Inactivation of Primary Human Immunodeficiency Virus Envelope Glycoprotein Trimers by CD4-Mimetic Compounds. J Virol 91:
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:

Showing the most recent 10 out of 146 publications