Lethal effects of ivermectin structures on malaria vectors and in silico analysis of interactions with their glutamate-gated chloride ion channels

TL;DR

This paper shows how ivermectin kills malaria-carrying mosquitoes by interacting with their chloride ion channels, and identifies a key hydrogen bond that could lead to resistance.

Contribution

The study identifies a novel hydrogen bond between ivermectin and Anopheles GluCl channels, explaining differential toxicity and resistance potential.

Findings

Ivermectin with two sugar rings is most lethal to Anopheles mosquitoes, while aglycone has no effect.

A hydrogen bond between ivermectin's 4″-OH and THR304 in Anopheles GluCl is crucial for toxicity.

A single amino acid substitution in the M2-M3 loop of GluCl explains differences in ivermectin sensitivity between species.

Abstract

Ivermectin is lethal to Anopheles mosquitoes making it a possible malaria control intervention. The primary mode of action of ivermectin occurs when it binds to the glutamate-gated chloride channel (GluCl), allowing for continuous flow of chloride leading to flaccid paralysis and death of the mosquito. In Caenorhabditis elegans, ivermectin is thought to open the GluCl channel when the M2-M3 loop forms Van der Waals bonds with the first sugar ring and aglycone structure of ivermectin. Here we investigate in Anopheles dirus and Anopheles minimus the mosquito-lethal effect of ivermectin (both sugar rings), monosaccharide (one sugar ring), and aglycone (no sugar rings) demonstrating full, partial, and no effect, respectively. The Anopheles GluCl protein sequences were determined and used to a create 3-D structural docking models. The docking models identified new binding interactions with a hydrogen bond forming between the second sugar ring hydroxyl group (4″-OH) and THR304 of the Anopheles GluCl M2-M3 loop. This hydrogen bond is possible due to a single substitution in the M2-M3 loop from C. elegans ILE273 to Anopheles THR304. The work presented here improves our understanding of Anopheles GluCl-ivermectin interactions as well as how ivermectin resistance could arise in the future.

The online version contains supplementary material available at 10.1038/s41598-026-39698-8.

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