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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

Corresponding Author:[email protected]

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Justyna CioleK
Commissariat a l'energie atomique et aux energies alternatives
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Christiane Mendre
cnrs
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Amélia Chorfa
cnrs
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Paola Huerta
Commissariat a l'energie atomique et aux energies alternatives
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Chrystelle Carvalho
Commissariat a l'energie atomique et aux energies alternatives
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Charlotte Gouin
Commissariat a l'energie atomique et aux energies alternatives
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Manon Lancien
Commissariat a l'energie atomique et aux energies alternatives
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Guillaume Blanchet
Commissariat a l'energie atomique et aux energies alternatives
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Gregory Upert
Commissariat a l'energie atomique et aux energies alternatives
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Edwin De Pauw
Liege University
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Peggy Barbe
Commissariat a l'energie atomique et aux energies alternatives
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Mathilde Keck
Commissariat a l'energie atomique et aux energies alternatives
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Gilles Mourier
Commissariat a l'energie atomique et aux energies alternatives
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Bernard Mouillac
cnrs
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Denis Servent
Commissariat a l'energie atomique et aux energies alternatives
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Ricardo Rodriguez-de-la-vega
CNRS
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Loïc Quinton
Liege University
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Nicolas Gilles
Commissariat a l'energie atomique et aux energies alternatives
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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.
01 Jul 2021Submitted to British Journal of Pharmacology
01 Jul 2021Submission Checks Completed
01 Jul 2021Assigned to Editor
03 Jul 2021Reviewer(s) Assigned
20 Jul 2021Review(s) Completed, Editorial Evaluation Pending
20 Jul 2021Editorial Decision: Revise Minor
13 Dec 20211st Revision Received
14 Dec 2021Submission Checks Completed
14 Dec 2021Assigned to Editor
23 Dec 2021Reviewer(s) Assigned
04 Jan 2022Review(s) Completed, Editorial Evaluation Pending
04 Jan 2022Editorial Decision: Revise Minor
05 Jan 20222nd Revision Received
07 Jan 2022Submission Checks Completed
07 Jan 2022Assigned to Editor
10 Jan 2022Review(s) Completed, Editorial Evaluation Pending
11 Jan 2022Editorial Decision: Accept
Jul 2022Published in British Journal of Pharmacology volume 179 issue 13 on pages 3470-3481. 10.1111/bph.15814