# Shapeshifting Cyclic Peptides as Single Molecule Polypharmacological Drugs

> **NIH NIH R21** · UNIVERSITY OF COLORADO · 2024 · $213,563

## Abstract

SUMMARY/ABSTRACT
For many years, scientists have been trying to find new therapeutic drugs. However, small molecules are still
imperfect tools for influencing human physiology. The chemical space that our known drugs occupy is extremely
small, representing a tiny sliver of the estimated 10^63 possible drug-like molecules. What’s more, the targets of
these drugs make up just about 3.5% of the roughly 20,000 proteins in the human proteome. This means almost
97% of the proteome is still untouched for drug intervention. These two factors suggest there’s immense potential
for discovering novel chemical structures to combat disease. However, systematically exploring such enormous
chemical spaces is physically unachievable. To synthesize even milligram scale representations of this chemical
space would result in a mass surpassing that of the known universe. This practical obstacle partly explains why
only a small portion of the proteins in the proteome have been pharmacologically targeted. To overcome this
diversity enumeration hurdle, we aim to introduce a completely new class of molecules capable of spontaneously
“shape shifting” at physiological temperature. This unique ability will allow them to assume a wide array of rapidly
interchanging structural isomers, essentially behaving like many molecules in one. We plan to demonstrate this
technology through the development of synthetic bullvalene amino acids that can be seamlessly incorporated
into existing methodologies for combinatorial solid phase peptide synthesis to create shape shifting cyclic
peptides (SSCP). Our ultimate goal is to create a dynamic and adaptable library that far outpaces any known
library in terms of diversity. We aim to utilize this technology to identify single molecular entities that display multi-
target pharmacological properties.

## Key facts

- **NIH application ID:** 10864699
- **Project number:** 1R21GM154148-01
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Michael H. B. Stowell
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $213,563
- **Award type:** 1
- **Project period:** 2024-09-05 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10864699

## Citation

> US National Institutes of Health, RePORTER application 10864699, Shapeshifting Cyclic Peptides as Single Molecule Polypharmacological Drugs (1R21GM154148-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10864699. Licensed CC0.

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