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Covalent capture of small molecule - gp41 complexes

Award Number: R21AI140904
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: 11/16/2018
PERIOD OF PERFORMANCE END DATE: 10/31/2022

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Covalent capture of small molecule - gp41 complexes - ABSTRACT This is an exploratory proposal to develop new anti-HIV compounds that will inhibit entry of the virus into human host cells by targeting gp41, the protein responsible for fusion of viral and host cell membranes. The project utilizes synthetic organic chemistry, NMR structure determination, computational docking and energy minimization, X-ray crystallography of protein – ligand complexes and biophysical and biological evaluation of potency and mechanism. The specific focus of the proposal is development of molecules with chemical reactive groups that can form covalent links with residues in the binding site. Recent research in this area has revealed the propensity for covalent association to dramatically increase the potency of small molecule inhibitors by extending the lifetime of the complexes formed with protein targets. The specific target on gp41 is a highly conserved hydrophobic pocket that is exposed during the process of fusion and plays a key role in stabilizing the post-fusion structure required for a successful fusion event. The hydrophobic pocket contains lysine, glutamine and threonine residues that will be the target of the covalent inhibitors. Boron chemistry will be used to generate reversible covalent bonds that stabilize the complexes but will avoid off-target effects and consequently potential toxicity. Development of low molecular weight fusion inhibitors has been an elusive but attractive goal, because of the potential to obtain orally available drugs that can prevent the initial infection of cells and are likely to have a high barrier to resistance. Thus the work proposed represents an important new direction towards developing nM small molecule inhibitors of fusion.


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: 2024 ( Subtotal = $0 )
2024	2020	TOURO UNIVERSITY	1310 CLUB DR	VALLEJO	CA	94592	SOLANO	USA	Allergy and Infectious Diseases Research	000	2	11/14/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	TOURO UNIVERSITY	1310 CLUB DR	VALLEJO	CA	94592	SOLANO	USA	Allergy and Infectious Diseases Research	000	2	10/18/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $178,750 )
2020	2020	TOURO UNIVERSITY	1310 JOHNSON	VALLEJO	CA	94592	SOLANO	USA	Allergy and Infectious Diseases Research	000	2	11/12/2019	NON-COMPETING CONTINUATION	$178,750
														Subtotal = $178,750

Issue Date FY: 2019 ( Subtotal = $214,500 )
2019	2019	TOURO UNIVERSITY	1310 CLUB DR	VALLEJO	CA	94592	SOLANO	USA	Allergy and Infectious Diseases Research	000	1	11/16/2018	NEW	$214,500
														Subtotal = $214,500

Grand Total All Awards = $393,250

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Covalent capture of small molecule - gp41 complexes

Award Number: R21AI140904

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: 11/16/2018

PERIOD OF PERFORMANCE END DATE: 10/31/2022

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