The Cyclic Imine Core Common to the Marine Macrocyclic Toxins Is Sufficient to Dictate Nicotinic Acetylcholine Receptor Antagonism

Author:

Bourne Yves1,Sulzenbacher Gerlind1,Chabaud Laurent2ORCID,Aráoz Rómulo3,Radić Zoran4,Conrod Sandrine5ORCID,Taylor Palmer4,Guillou Catherine2ORCID,Molgó Jordi3ORCID,Marchot Pascale15ORCID

Affiliation:

1. Lab “Architecture et Fonction des Macromolécules Biologiques” (AFMB), Aix-Marseille Univ, CNRS, Faculté des Sciences Campus Luminy, 13288 Marseille cedex 09, France

2. Institut de Chimie des Substances Naturelles (ICSN), Univ Paris-Saclay, CNRS, 91198 Gif-sur-Yvette, France

3. Service d’Ingénierie Moléculaire pour la Santé (SIMoS) EMR CNRS 9004, Département Médicaments et Technologies pour la Santé, Institut des Sciences du Vivant Frédéric Joliot, CEA, INRAE, Université Paris-Saclay, 91191 Gif-sur-Yvette, France

4. Skaggs School of Pharmacy and Pharmaceutical Sciences (SSPPS), University of California San Diego, La Jolla, CA 92093-0751, USA

5. Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille (CRN2M), Aix Marseille Univ, CNRS, 13344 Marseille, France

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 substantial antagonism, binding affinities, and receptor-subtype selectivity. Earlier, complementary crystal structures of AChBP complexes 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 toward peripheral subsites, dictate broad versus narrow receptor subtype selectivity. From these data, small spiroimine enantiomers mimicking the functional core motif of phycotoxins were chemically synthesized and characterized. Voltage-clamp analyses involving three nAChR subtypes revealed preserved antagonism for both enantiomers, despite lower subtype specificity and binding affinities associated with faster reversibility compared with their macrocyclic relatives. Binding and structural analyses involving two AChBPs pointed to modest affinities and positional variability of the spiroimines, along with a range of AChBP loop-C conformations denoting a prevalence of antagonistic 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 marked subtype specificity. This study identifies a minimal set of functional pharmacophores and binding determinants as templates for designing new antagonists targeting disease-associated nAChR subtypes.

Funder

Agence Nationale de la Recherche

ISCN-CNRS

United States Public Health Service

Publisher

MDPI AG

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