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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-AARR-E)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Drexel University
United States
Zip Code
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:
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:
Rashad, Adel A; Acharya, Kriti; Haftl, Ann et al. (2017) Chemical optimization of macrocyclic HIV-1 inactivators for improving potency and increasing the structural diversity at the triazole ring. Org Biomol Chem 15:7770-7782

Showing the most recent 10 out of 146 publications