Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Probing functional HIV-1 envelope glycoprotein conformations with novel potent CD4-mimetic compounds

Award Number: R01AI176904
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/10/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2027

Group Awards By:

View Award Description

Probing functional HIV-1 envelope glycoprotein conformations with novel potent CD4-mimetic compounds - PROJECT SUMMARY/ABSTRACT The human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer ((gp120-gp41)3) binds to host receptors, CD4 and CCR5/CXCR4, and mediates the entry of the virus into the target cell. CD4 binding induces large-scale conformational changes in the metastable Env trimer, resulting in transitions from a pretriggered, “closed” conformation to more “open” conformations. The CD4-induced opening of the Env trimer allows the gp120 subunit to bind the CCR5/CXCR4 coreceptor, which enables the fusion of viral and target cell membranes by the gp41 transmembrane subunit. CD4-mimetic compounds (CD4mcs) are small organic molecules that bind to a highly conserved pocket (the Phe-43 cavity) on gp120, near the binding site for CD4. CD4mcs competitively block CD4 binding and prematurely trigger conformational changes in Env similar to those induced by CD4. In the absence of a coreceptor-expressing target cell, these prematurely activated Envs rapidly and irreversibly become non- functional. At sub-inhibitory concentrations, CD4mcs open Env to the binding of antibodies that consequently acquire neutralizing or cytotoxic potential. CD4mcs can synergize with antibodies to decrease the HIV-1-infected cell reservoir in humanized mice and to protect monkeys from a heterologous SHIV mucosal challenge. The CD4mc scaffold, which occupies the gp120 “vestibule” leading into the Phe-43 cavity, is a critical determinant of the antiviral potential of these compounds. Replacing the tetramethyl-piperidine scaffold of the prototypic CD4mcs with an indane scaffold opened the door to rationally designed improvements in antiviral potency and breadth. Nonetheless, some primary HIV-1 strains with apparently accessible Phe-43 cavities remain relatively resistant to current lead indane CD4mcs. We have recently identified novel CD4mc analogues with indoline scaffolds that demonstrate impressive increases in antiviral potency and breadth. In this proposal, we capitalize on this discovery to design further improvements in the indoline CD4mcs, to investigate the mechanisms underlying their antiviral potency, and to determine how natural HIV-1 Env variation influences virus resistance to CD4mcs and viral replication fitness. In the course of these studies, we will test the following hypotheses: Hypothesis 1: Increasing the contacts of the indoline CD4mcs with conserved gp120 elements in the vestibule will further enhance their antiviral potency and breadth; Hypothesis 2: Although CD4mc resistance in a small subset of HIV-1 strains results from variation within the Phe-43 cavity, the sensitivity of most primary HIV-1 strains to CD4mcs is governed by differences in Env triggerability (the propensity of the Env to undergo conformational change); and Hypothesis 3: CD4mcs gain potency by enhanced binding to the Env trimer, leading to sequential activation and inactivation that ultimately result in gp120 shedding. The knowledge generated by testing these hypotheses will assist efforts to improve the antiviral efficacy of CD4mcs and will enhance their utility as small-molecule probes of HIV-1 Env conformation.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $825,965 )
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	6/30/2026	NON-COMPETING CONTINUATION	$825,965
														Subtotal = $825,965

Issue Date FY: 2025 ( Subtotal = $825,965 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	3	7/31/2025	NON-COMPETING CONTINUATION	$825,965
2025	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	6/27/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $825,965

Issue Date FY: 2024 ( Subtotal = $825,965 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	6/12/2024	NON-COMPETING CONTINUATION	$825,965
														Subtotal = $825,965

Issue Date FY: 2023 ( Subtotal = $889,028 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	7/10/2023	NEW	$889,028
														Subtotal = $889,028

Grand Total All Awards = $3,366,923

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Probing functional HIV-1 envelope glycoprotein conformations with novel potent CD4-mimetic compounds

Award Number: R01AI176904

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/10/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer