Shapeshifting Cyclic Peptides as Single Molecule Polypharmacological Drugs

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.