# Overlooked Complications and Opportunities in the Development of Drugs Based upon Macrobicyclic Peptides: The “Homeomorphic Switch”

## 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.

## Key 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.