From Functional Fatty Acids to Potent and Selective Natural-Product-Inspired Mimetics via Conformational Profiling.
| Autor: | Markham LE; Department of Chemistry, Dartmouth College, 6128 Burke Laboratory, Hanover, New Hampshire 03755, United States., Koelblen T; University of Florida Genetics Institute, P.O. Box 103610, 2033 Mowry Road, Gainesville, Florida 32610, United States., Chobanian HR; ROME Therapeutics, 201 Brookline Avenue, Suite 1001, Boston, Massachusetts 02215, United States., Follis AV; ROME Therapeutics, 201 Brookline Avenue, Suite 1001, Boston, Massachusetts 02215, United States., Burris TP; University of Florida Genetics Institute, P.O. Box 103610, 2033 Mowry Road, Gainesville, Florida 32610, United States., Micalizio GC; Department of Chemistry, Dartmouth College, 6128 Burke Laboratory, Hanover, New Hampshire 03755, United States. |
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| Jazyk: | angličtina |
| Zdroj: | ACS central science [ACS Cent Sci] 2024 Feb 12; Vol. 10 (2), pp. 477-486. Date of Electronic Publication: 2024 Feb 12 (Print Publication: 2024). |
| DOI: | 10.1021/acscentsci.3c01155 |
| Abstrakt: | Fatty acids play important signaling roles in biology, albeit typically lacking potency or selectivity, due to their substantial conformational flexibility. While being recognized as having properties of potentially great value as therapeutics, it is often the case that the functionally relevant conformation of the natural fatty acid is not known, thereby complicating efforts to develop natural-product-inspired ligands that have similar functional properties along with enhanced potency and selectivity profiles. In other words, without structural information associated with a particular functional relationship and the hopelessly unbiased conformational preferences of the endogenous ligand, one is molecularly ill-informed regarding the precise ligand-receptor interactions that play a role in driving the biological activity of interest. To address this problem, a molecular strategy to query the relevance of distinct subpopulations of fatty acid conformers has been established through "conformational profiling", a process whereby a unique collection of chiral and conformationally constrained fatty acids is employed to deconvolute beneficial structural features that impart natural-product-inspired function. Using oleic acid as an example because it is known to engage a variety of receptors, including GPR40, GPR120, and TLX, a 24-membered collection of mimetics was designed and synthesized. It was then demonstrated that this collection contained members that have enhanced potency and selectivity profiles, with some being clearly biased for engagement of the GPCRs GPR40 and GPR120 while others were identified as potent and selective modulators of the nuclear receptor TLX. A chemical synthesis strategy that exploited the power of modern technology for stereoselective synthesis was critical to achieving success, establishing a common sequence of bond-forming reactions to access a disparate collection of chiral mimetics, whose conformational preferences are impacted by the nature of stereodefined moieties differentially positioned about the C Competing Interests: The authors declare no competing financial interest. (© 2024 The Authors. Published by American Chemical Society.) |
| Databáze: | MEDLINE |
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