# Peptides and Small-molecules Targeting Signaling Proteins and Protein-Protein Interfaces

> **NIH NIH R35** · UNIVERSITY OF NEW HAMPSHIRE · 2020 · $351,965

## Abstract

Cell-surface receptors and intracellular regulatory proteins are preeminent mediators of cellular
signaling as these proteins are involved in a host of interactions and pathways. Therefore,
various stages of their signaling cycles provide unique opportunities for therapeutic intervention.
This project presents computational studies integrated with experimental data to resolve the
mechanisms of recognition of novel peptide mimetics and analogues targeting extracellular
domains of receptor proteins of the insulin family and small-molecules targeting intracellular
protein-protein interactions in regulatory proteins of the G-protein coupled receptor (GPCR)
family. The proposed studies are timely in that several recent structural studies have revealed
the binding modes of the native hormone insulin and homologous growth factor peptides and we
have developed dynamics-based computational approaches that have opened the avenues for
designing novel peptide-based agonists and antagonists. Toward this direction are our
proposed studies of three classes of peptides: (1) synthetic insulin mimetics, (2) viral-insulin-like
peptides (VILPs), and insulin-like peptides from cone snail venom. Our second research
direction aims to develop small-molecule inhibitors targeting a key intracellular protein-protein
interaction between regulators of G-protein signaling (RGS) proteins and the alpha-subunits of
G-proteins. As opposed to the conventional approach of directly targeting the protein-protein
interface, we propose to target allosteric sites on RGS proteins to inhibit the protein-protein
interaction. Through preliminary studies on a model protein, we have shown that allosteric
control and targeting is feasible and through this project we propose to broaden the scope of
these promising studies to new protein targets involved in cancer and visual signaling. Overall,
we anticipate that the mechanistic paradigms emerging from these studies will have broader
applicability to other protein families and will facilitate the design of novel therapeutic strategies.

## Key facts

- **NIH application ID:** 10029419
- **Project number:** 1R35GM138217-01
- **Recipient organization:** UNIVERSITY OF NEW HAMPSHIRE
- **Principal Investigator:** Harish Vashisth
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $351,965
- **Award type:** 1
- **Project period:** 2020-09-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10029419

## Citation

> US National Institutes of Health, RePORTER application 10029419, Peptides and Small-molecules Targeting Signaling Proteins and Protein-Protein Interfaces (1R35GM138217-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10029419. Licensed CC0.

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