loading page

A new Kunitz-type snake toxin family associated with an original mode of interaction with the vasopressin 2 receptor.
  • +16
  • Laura Droctové,
  • Justyna CioleK,
  • Christiane Mendre,
  • Amélia Chorfa,
  • Paola Huerta,
  • Chrystelle Carvalho,
  • Charlotte Gouin,
  • Manon Lancien,
  • Guillaume Blanchet,
  • Gregory Upert,
  • Edwin De Pauw,
  • Peggy Barbe,
  • Mathilde Keck,
  • Gilles Mourier,
  • Bernard Mouillac,
  • Denis Servent,
  • Ricardo Rodriguez-de-la-vega,
  • Loïc Quinton,
  • Nicolas Gilles
Laura Droctové
Commissariat a l'energie atomique et aux energies alternatives
Author Profile
Justyna CioleK
Commissariat a l'energie atomique et aux energies alternatives
Author Profile
Christiane Mendre
cnrs
Author Profile
Amélia Chorfa
cnrs
Author Profile
Paola Huerta
Commissariat a l'energie atomique et aux energies alternatives
Author Profile
Chrystelle Carvalho
Commissariat a l'energie atomique et aux energies alternatives
Author Profile
Charlotte Gouin
Commissariat a l'energie atomique et aux energies alternatives
Author Profile
Manon Lancien
Commissariat a l'energie atomique et aux energies alternatives
Author Profile
Guillaume Blanchet
Commissariat a l'energie atomique et aux energies alternatives
Author Profile
Gregory Upert
Commissariat a l'energie atomique et aux energies alternatives
Author Profile
Edwin De Pauw
Liege University
Author Profile
Peggy Barbe
Commissariat a l'energie atomique et aux energies alternatives
Author Profile
Mathilde Keck
Commissariat a l'energie atomique et aux energies alternatives
Author Profile
Gilles Mourier
Commissariat a l'energie atomique et aux energies alternatives
Author Profile
Bernard Mouillac
cnrs
Author Profile
Denis Servent
Commissariat a l'energie atomique et aux energies alternatives
Author Profile
Ricardo Rodriguez-de-la-vega
CNRS
Author Profile
Loïc Quinton
Liege University
Author Profile
Nicolas Gilles
Commissariat a l'energie atomique et aux energies alternatives
Author Profile

Abstract

Background and purpose. Venomous animals express numerous Kunitz-type peptides. The mambaquaretin-1 (MQ1) recently identified from the Dendroaspis angusticeps venom is the most selective antagonist of the arginine-vasopressin V2 receptor (V2R) and the unique Kunitz-type peptide active on a GPCR. We aimed to exploit other mamba venoms to enlarge the V2R-Kunitz peptide family and get 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. Several newly identified MQs were produced by solid phase peptide synthesis. They were characterized in vitro by binding and functional tests andin 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 2 V2R active cobra toxins. Sequence comparison between active and non-active V2R Kunitz peptides highlighted 5 specific V2R positions. Four of them are involved in V2R activity and belong to the 2 large MQ1 loops. We finally determined that 8 positions, part of these 2 loops, interact with the V2R. The variant MQ1-K39A showed specificity for the human versus the rat V2R . Conclusions and implications. A third function and mode of action is now 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 for medicinal perspective.

Peer review status:IN REVISION

01 Jul 2021Submitted to British Journal of Pharmacology
01 Jul 2021Assigned to Editor
01 Jul 2021Submission Checks Completed
03 Jul 2021Reviewer(s) Assigned
20 Jul 2021Review(s) Completed, Editorial Evaluation Pending
20 Jul 2021Editorial Decision: Revise Minor