The goal of this Program Project is the discovery, design, synthesis, optimization and validation of small molecule antagonists of the HIV-1 envelope (Env) trimer, combined with the definition of their molecular, virological and cellular mechanisms of action to identify potential preventive and therapeutic approaches to attack the HIV- 1/AIDS pandemic. The HIV-1 Env trimer is the only virus-specific protein on both the exposed surface of HIV-1 virions and on HIV-1 infected cells, and as such is a crucial first target for prevention and intervention of virus infection. Compounds that can bind with sufficient affinity, specificity and breadth to sequence-conserved and functional centers on Env should be able to inhibit, inactivate, and/or prematurely activate Env on the virus and on infected cells. In so doing, such compounds could block both cell infection and the formation of new infectious viruses, and prime infected cells for eradication. Major advancements have been made in our Program Project during the past 5 years to identify small molecule HIV-1 Env inhibitors that [1] allosterically or competitively block HIV-1 cell receptor interactions and cell infection; [2] irreversibly inactivate both the virus and virus-infected cells; and [3] sensitize cells to antibody-mediated immune responses. This progress opens up important opportunities to identify and explore the fundamental mechanisms of Env antagonism. Our progress going forward in developing small molecule inhibitors will be greatly facilitated by a deepening understanding of conformational states, dynamics and high-resolution structures of the HIV-1 Env trimer, as well as an understanding of how this molecular machine is activated to mediate fusion between viral and cellular membranes. In turn, the understanding of Env trimer structure and dynamics will be aided by small molecule inhibitors, developed by our Program Project, that function as chemical probes to inhibit, entrap or activate specific conformational states. The discovery, design, synthesis, optimization and validation of small molecules will enhance the identification of preventive, therapeutic and eradication interventions for HIV-1/AIDS. We will pursue a comprehensive mechanistic approach to investigate HIV-1 Env antagonism. To accomplish this, 7 investigators organized in 5 projects and 3 cores will pursue a multi-disciplinary integrated and synergistic approach. Knowing that no single group can succeed alone, the program has established a highly collaborative and efficient infrastructure, with an atmosphere where ideas are discussed early, new findings exchanged quickly, and the most effective strategies validated in order to fulfill the research goals. This Program Project will build both on an experienced group of investigators as well as the two new investigators to respond to new developments and challenges.

Public Health Relevance

The goal of this Program Project is to discover, design, synthesize, optimize and validate small molecule Env antagonists, and to determine their molecular, virological and cellular mechanisms of action to define rational approaches for prevention, therapeutic intervention and eradication of the HIV-1/AIDS pandemic.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
2P01GM056550-22
Application #
9561488
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sakalian, Michael
Project Start
1997-08-01
Project End
2023-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
22
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Drexel University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19102
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:
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
Herschhorn, Alon; Gu, Christopher; Moraca, Francesca et al. (2017) The ?20-?21 of gp120 is a regulatory switch for HIV-1 Env conformational transitions. Nat Commun 8:1049

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