posted on 2024-02-12, 17:07authored byLauren
E. Markham, Thomas Koelblen, Harry R. Chobanian, Ariele Viacava Follis, Thomas P. Burris, Glenn C. Micalizio
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 C18 skeleton
of the parent fatty acid. Overall, this study establishes a foundation
to fuel future programs aimed at developing natural-product-inspired
fatty acid mimetics as valuable tools in chemical biology and potential
therapeutic leads.