Overlooked Complications and Opportunities in the Development of Drugs Based upon Macrobicyclic Peptides: The “Homeomorphic Switch”
Isabelle J. Smith, Simon M. Popovic, John A. Gladysz
TL;DR
This paper discusses a conformational process in macrobicyclic peptides that can change their properties and offers new opportunities for drug design and patent strategies.
Contribution
The paper introduces the concept of homeomorphic isomerization in macrobicyclic peptides and its implications for drug development.
Findings
Macrobicyclic compounds can undergo homeomorphic isomerization, leading to different bridgehead configurations.
This process can result in varied chemical and biological properties of the molecules.
Opportunities exist for improving drug design and addressing patent issues.
Abstract
Many macrobicyclic compounds can undergo a widely overlooked conformational process, homeomorphic isomerization, that effectively turns molecules inside-out and leads to species with in,in, out,out, in,out, and out,in bridgeheads. Different chemical and biological properties would be expected. Some foundational aspects of this phenomenon are briefly reviewed, with both model compounds of the formula E((CH2) n )3E (n ≥ 10, E = P, As, etc.) and macrobicyclic peptides. Attempts are made to bridge the differing cultural perspectives of the physical organic and chemical biology communities regarding bicyclic molecules. Opportunities are presented for (1) improving the stereochemical definition of macrobicyclic peptides and their adducts with proteins, (2) new drug design and efficacy protocols, and (3) refining or circumventing existing patented IP.
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Taxonomy
TopicsChemical Synthesis and Analysis · Click Chemistry and Applications · Carbohydrate Chemistry and Synthesis