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Development of a novel proximity catalyzed Chemical Epitope Targeting technology for isolating macrocyclic peptide inhibitors of KRas(G12V)-Sos interaction

Award Number: R15GM139155
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/10/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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Development of a novel proximity catalyzed Chemical Epitope Targeting technology for isolating macrocyclic peptide inhibitors of KRas(G12V)-Sos interaction - ABSTRACT Protein function modifications for therapeutic purposes are typically accomplished with small molecule drugs that bind in deep hydrophobic pockets of proteins. For protein-protein interactions occurring over an extended shallow area, it is challenging to have small molecules binding to the surface area and thereby affecting protein functions. Ras -Sos is a classic example of extensive protein-protein surface interaction, and therefore it remains challenging to inhibit KRas- Sos interactions. KRas is activated by Sos, and it is critical to develop technologies to inhibit interactions of oncogenic mutant KRas with Sos selectively. One such promising technology is the Chemical Epitope Targeting technology, developed for designing peptide ligands with high affinity and specificity against specific regions of an intracellular protein that may be inaccessible to small molecules or antibodies. This technology involves using proximity-catalyzed reaction for screening a specific region of the target protein to isolate peptide ligands. The PI proposes to streamline this technology to make it more accessible and user-friendly, and then to tailor this technology to successfully target mutant KRas(G12V) protein, specifically at the Ras-Sos interface. The technology will be streamlined by developing and characterizing synthetic macrocyclic one-bead-one compound (OBOC) peptide libraries that can be cleaved by one-step light exposure for seamless sequencing by tandem Mass Spectrometry (MS/MS) (Aim 1). Inverse Electron Demand Diels-Alder (IEDDA) reaction between tetrazine and alkene will be used for the screening process rather than the currently used azide-alkyne cycloaddition. The PI shall demonstrate, as a proof-of-concept, that IEDDA reaction between substituted tetrazine and an alkene can be proximity-catalyzed by a protein. KRas(G12C) or KRas mutants with one Cys will be modified at Cys with tetrazine. The labeling of the complex with an alkene containing Sos-helix peptide, known to bind at the Ras- Sos interface, will be monitored using tandem Mass Spectrometry (Aim 2). The optimal temperature for minimal background IEDDA reaction between tetrazine and alkene will be identified, to minimize background for the screen in the next step. A Chemical Epitope Targeting screen against the Chemical Epitope, KRas(G12V) complexed to a GDP- alkene small molecule, will be performed using S,S-tetrazine cyclized OBOC peptide libraries (Aim 3). Screening for inhibition of KRas(G12V)-Sos interaction using a split luciferase platform will follow. Aims 1 and 2 should be achieved, and Aim 3 be initiated within the grant period. This project, being multidisciplinary, will allow the PI to train undergraduate and graduate students at Clark University in a variety of chemical and biochemical techniques.


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: 2025 ( Subtotal = $0 )
2025	2020	TRUSTEES OF CLARK UNIVERSITY	950 MAIN ST	WORCESTER	MA	01610	WORCESTER	USA	Biomedical Research and Research Training	000	1	1/29/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	TRUSTEES OF CLARK UNIVERSITY	950 MAIN ST	WORCESTER	MA	01610	WORCESTER	USA	Biomedical Research and Research Training	000	1	9/8/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $450,862 )
2020	2020	TRUSTEES OF CLARK UNIVERSITY	950 MAIN ST	WORCESTER	MA	01610	WORCESTER	USA	Biomedical Research and Research Training	000	1	9/2/2020	NEW	$450,862
														Subtotal = $450,862

Grand Total All Awards = $450,862

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Development of a novel proximity catalyzed Chemical Epitope Targeting technology for isolating macrocyclic peptide inhibitors of KRas(G12V)-Sos interaction

Award Number: R15GM139155

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/10/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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