4.7 Article

A new Kunitz-type snake toxin family associated with an original mode of interaction with the vasopressin 2 receptor

Journal

BRITISH JOURNAL OF PHARMACOLOGY
Volume 179, Issue 13, Pages 3470-3481

Publisher

WILEY
DOI: 10.1111/bph.15814

Keywords

antagonist; Kunitz peptide; peptide sequencing; peptide synthesis; proteomics; snake venom; V2R

Funding

  1. Commissariat a l'E nergie Atomique et aux Energies Alternatives
  2. Ligue Contre le Cancer

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This study identified 8 novel mambaquaretin-1 (MQ1) peptides with nanomolar affinities for the V2R, all of which act as antagonists. These MQs form a new subgroup in the Kunitz family, closely related to the non-active dendrotoxins and two V2R-active cobra toxins. Sequence comparison between active and non-active V2R Kunitz peptides revealed key positions involved in V2R interaction. The MQ1-K39A variant showed a higher affinity for the human V2R.
Background and Purpose Venomous animals express numerous Kunitz-type peptides. The mambaquaretin-1 (MQ1) peptide identified from the Dendroaspis angusticeps venom is the most selective antagonist of the arginine-vasopressin V2 receptor (V2R) and the only unique Kunitz-type peptide active on a GPCR. We aimed to exploit other mamba venoms to enlarge the V2R-Kunitz peptide family and gain insight into the MQ1 molecular mode of action. Experimental Approach We used a bio-guided screening assay to identify novel MQs and placed them phylogenetically. MQs were produced by solid-phase peptide synthesis and characterized in vitro by binding and functional tests and in vivo by diuresis measurement in rats. Key Results Eight additional MQs were identified with nanomolar affinities for the V2R, all antagonists. MQs form a new subgroup in the Kunitz family, close to the V2R non-active dendrotoxins and to two V2R-active cobra toxins. Sequence comparison between active and non-active V2R Kunitz peptides highlighted five positions, among which four are involved in V2R interaction and belong to the two large MQ1 loops. We finally determined that eight positions, part of these two loops, interact with the V2R. The variant MQ1-K39A showed a higher affinity for the hV2R, but not for the rat V2R. Conclusions and Implications A new function and mode of action is associated with the Kunitz peptides. The number of MQ1 residues involved in V2R binding is large and may explain its absolute selectivity. MQ1-K39A represents the first step in the improvement of the MQ1 design from a medicinal perspective.

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