Guanylate cyclase activator

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A guanylate cyclase activator (or "GUCA") is a member of a group of proteins that upregulate guanylate cyclase. GUCA is also known as guanylate cyclase-activating protein (or "GCAP"). Its mutations can be associated with vision defects. [1]

There are five genes involved:

There are several therapeutic drugs that act as GUCAs, including linaclotide and plecanatide, which are guanylate cyclase-C receptor agonists. These drugs increase the secretion of bicarbonate and chloride in the colon and potentially relieve visceral hypersensitivity in IBS-C patients. [2]

Guanyl cyclase targeting drug, Cinaciguat has emerged in recent years as one of the first in the class of soluble guanyl cyclase activator. Soluble guanyl class is a version of guanyl cyclase that has a primary preference for nitric oxide(NO) sensitivity, with some variants beings more insensitive to NO than others but still remaining soluble within the cell cytosol. [3] Cinaciguat targets the specifically the soluble form of guanyl cyclase. This guanyl that triggers reduced blood flow through GTP to cGMP conversion. The cGMP acts as a secondary messenger to target reduced blood flow pathways. This pathway has been linked to several cardiovascular diseases, such as ADHF(acute decompensated heart failure) which Cinaciguat has been developed to target. [4]

References

  1. Payne AM, Downes SM, Bessant DA, et al. (1998). "A mutation in guanylate cyclase activator 1A (GUCA1A) in an autosomal dominant cone dystrophy pedigree mapping to a new locus on chromosome 6p21.1". Hum. Mol. Genet. 7 (2): 273–7. doi: 10.1093/hmg/7.2.273 . PMID   9425234.
  2. Saps, Miguel; Miranda, Adrian (2017), Greenwood-Van Meerveld, Beverley (ed.), "Gastrointestinal Pharmacology" , Handbook of Experimental Pharmacology, 239, Cham: Springer International Publishing: 147–176, doi:10.1007/164_2016_119, ISBN   978-3-319-56359-6, PMID   28236087 , retrieved 2024-04-27
  3. Estancial, Camila S.; Rodrigues, Renata L.; De Nucci, Gilberto; Antunes, Edson; Mónica, Fabiola Z. (2015). "Pharmacological characterisation of the relaxation induced by the soluble guanylate cyclase activator, BAY 60-2770 in rabbit corpus cavernosum" . BJU International. 116 (4): 657–664. doi:10.1111/bju.13105. ISSN   1464-410X. PMID   25715977.
  4. Sawabe, Toshihiro; Chiba, Toshiki; Kobayashi, Akihiro; Nagasaka, Kosuke; Aihara, Kazuyuki; Takaya, Akiyuki (2019). "A novel soluble guanylate cyclase activator with reduced risk of hypotension by short-acting vasodilation". Pharmacology Research & Perspectives. 7 (2): e00463. doi:10.1002/prp2.463. ISSN   2052-1707. PMC   6399102 . PMID   30873284.