Conference Papers Year : 2024

Is the cyclic imine core common to the marine macrocyclic toxins sufficient to dictate nicotinic acetylcholine receptor antagonism?

Abstract

Macrocyclic imine phycotoxins are an emerging class of chemical compounds associated with harmful algal blooms and shellfish toxicity. Earlier binding and electrophysiology experiments on nAChR subtypes and their soluble AChBP surrogates evidenced common trends for prominent antagonism, binding affinities, and receptorsubtype selectivity. Earlier, complementary crystal structures of AChBP complexes with phycotoxins showed that common determinants within the binding nest at each subunit interface confer high-affinity toxin binding, while distinctive determinants from the flexible loop C, and either capping the nest or extending towards peripheral subsites, dictate broad versus narrow receptor subtype selectivity [1,2,3]. From these data, small spiroimine enantiomers mimicking the functional core motif of CiTXs were chemically synthesized and characterized. Voltage-clamp analyses involving three nAChRs revealed preserved antagonism for both enantiomers, despite lower binding affinities and subtype specificity, compared with their macrocyclic relatives. Binding and structural analyses involving two AChBPs pointed to positional variability of the spiroimines along with a range of loop-C conformations, suggesting mixed agonist/antagonist properties. These data highlight the major contribution of the spiroimine core to binding within the nAChR nest and confirm the need for an extended interaction network as established by the macrocyclic toxins to define high affinities and subtype specificity [4]. Hence, this study identifies a minimal set of functional pharmacophores and binding determinants as templates for designing new effectors targeting disease-associated nAChR subtypes.

Dates and versions

hal-04797916 , version 1 (22-11-2024)

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Yves Bourne, Gerlind Sulzenbacher, Laurent Chabaud, Rómulo Aráoz, Zoran Radić, et al.. Is the cyclic imine core common to the marine macrocyclic toxins sufficient to dictate nicotinic acetylcholine receptor antagonism?. Report from the 29th Meeting on Toxinology, “Toxins: From the Wild to the Lab”, Organized by the French Society of Toxinology on 30 November–1 December 2023, SFET, Nov 2023, Paris, France. pp.147 (16-17), ⟨10.3390/toxins16030147⟩. ⟨hal-04797916⟩
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