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

Many macrobicyclic compounds can undergo a widely overlooked conformational process, homeomorphic isomerization, that effectively turns molecules inside-out and leads to species with <i>in,in</i>, <i>out,out</i>, <i>in,out</i>, and <i>out,in</i> 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)_<i>n</i>)₃E (<i>n</i> ≥ 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.