Proceedings - Boulder Peptide Foundation

BPS 2025

A snake peptide toxin for treatment of kidney diseases. From bench to bedside

Nicolas Gilles

senior researcher, CEA

ABSTRACT

The kidney regulates many physiological roles like water homeostasis, expertly managed by the vasopressin type 2 receptor (V2R). Positioned within the kidney’s collecting tubule, this membrane receptor responds to the peptide hormone, the vasopressin. The V2R activation triggers the generation of the secondary messenger cyclic adenosine monophosphate (cAMP). cAMP induces urine concentration in alignment with the body’s requirements.
Two pathological conditions, hyponatremia and polycystic diseases are addressed by blocking the V2R and since the 1980s, pharmaceutical enterprises developed the “vaptans”. Regrettably, the majority of vaptans exhibited hepatotoxicity concerns, and only the tolvaptan (Otsuka Pharma) is used but with many concerns, leaving millions of untreated patients.
Animal venoms are an extraordinary source of potent and natural peptide toxins. A comprehensive screening of venoms against the V2R led to the revelation of a novel cluster of snake toxins within the Kunitz-type peptide family. Among these, the MQ1 toxin emerged as a standout due to its remarkable pharmacological properties. Evaluation within rodent models of hyponatremia and polycystic diseases revealed its promise. Subsequent efforts involved refining the MQ1’s characteristics in term of risk of immunogenicity and affinity. The generated MQ232, a 57 residues peptide reticulated by 3 disulfide bridges and produce by solid phase synthesis, boasts a therapeutic window of over 100. With all the hallmarks of a groundbreaking solution, MQ232 is poised to address unmet medical needs.
Embarking on the path to clinical validation, the startup V4Cure, specializing in leveraging animal toxins within the cardio-renal axis, supports MQ232 into human assessment.

BIO

Full time researcher at the Department of Medicines and Technologies for Health, in the Toxins Receptors and Ion channels team. In charge of the identification and therapeutic development of animal toxins active on G-Protein Coupled Receptors for human benefit.

Dr. Nicolas Gilles is an expert in the study of animal toxins. He is pioneering the investigation of animal toxins acting on GPCRs, the largest therapeutic target class. His strongest expertise lies in therapeutic target identification and all the steps from venom manipulations, to in vivo validation. When the pharmacological properties of these new ligands are deemed exceptional, a lead optimization is realized and its therapeutic development initiates through a dedicated start-up. V4Cure, a CEA spin-off, is currently developing the V4C-232 for kidneys diseases.

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