The kidney, an intricately structured organ with multifaceted functions, regulates many physiological roles. Among these, a pivotal task involves maintaining water homeostasis, expertly managed by the vasopressin type 2 receptor (V2R). Positioned within the kidney's collecting tubule, this membrane receptor responds to the anti-diuretic 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 physiological and pathological conditions, hyponatremia and polycystic diseases are addressed by blocking the V2R. Since the 1980s, pharmaceutical enterprises embarked on the development of "vaptans," aiming to antagonize the V2R. Regrettably, the majority of vaptans exhibited hepatotoxicity concerns, and only the tolvaptan (Otsuka Pharma) managed to navigate the hurdles to reach the market. Tolvaptan is used but with many concerns, leaving millions of untreated patients.
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 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.