Chemistry:Aloxistatin

From HandWiki

Aloxistatin (loxistatin, E-64d, EST) is a drug which acts as a cysteine protease inhibitor and has anticoagulant effects. It is a synthetic analogue of E-64, a natural product derived from fungi.[1][2][3] It was researched for the treatment of muscular dystrophy but was not successful in human clinical trials,[4] though it has continued to be investigated for treatment of spinal cord injury, stroke and Alzheimer's disease.[5][6][7][8][9]

Aloxistatin also shows antiviral effects.[10][11][12] Studies have shown it can inhibit cathepsin L, a protein believed to play a role in SARS-CoV-2 cellular entry. In a laboratory study using SARS-CoV-2 pseudovirions, aloxistatin was able to reduce viral entry into cells by approximately 92%.[13][14]

References

  1. ↑ "In vitro and in vivo inhibition of cysteine proteinases by EST, a new analog of E-64". Journal of Pharmacobio-Dynamics 9 (8): 672–7. August 1986. doi:10.1248/bpb1978.9.672. PMID 3023601. 
  2. ↑ "Efficient synthetic method for ethyl (+)-(2S,3S)-3-[(S)-3-methyl- 1-(3-methylbutylcarbamoyl)butylcarbamoyl]-2-oxiranecarb oxylate (EST), a new inhibitor of cysteine proteinases". Chemical & Pharmaceutical Bulletin 35 (3): 1098–104. March 1987. doi:10.1248/cpb.35.1098. PMID 3301019. 
  3. ↑ "Design, Synthesis, and Structure-Activity Relationship Study of Epoxysuccinyl-Peptide Derivatives as Cathepsin B Inhibitors". Biological & Pharmaceutical Bulletin 40 (8): 1240–1246. August 2017. doi:10.1248/bpb.b17-00075. PMID 28502922. 
  4. ↑ "Therapeutic trials on progressive muscular dystrophy". Internal Medicine 31 (7): 841–6. July 1992. doi:10.2169/internalmedicine.31.841. PMID 1450492. 
  5. ↑ "Cell death in spinal cord injury (SCI) requires de novo protein synthesis. Calpain inhibitor E-64-d provides neuroprotection in SCI lesion and penumbra". Annals of the New York Academy of Sciences 939: 436–49. June 2001. doi:10.1111/j.1749-6632.2001.tb03655.x. PMID 11462799. 
  6. ↑ "Neurovascular and neuronal protection by E64d after focal cerebral ischemia in rats". Journal of Neuroscience Research 84 (4): 832–40. September 2006. doi:10.1002/jnr.20977. PMID 16802320. 
  7. ↑ "Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease". The Journal of Clinical Investigation 118 (8): 2796–807. August 2008. doi:10.1172/JCI34254. PMID 18596919. 
  8. ↑ "The cysteine protease inhibitor, E64d, reduces brain amyloid-β and improves memory deficits in Alzheimer's disease animal models by inhibiting cathepsin B, but not BACE1, β-secretase activity". Journal of Alzheimer's Disease 26 (2): 387–408. 2011. doi:10.3233/JAD-2011-110101. PMID 21613740. 
  9. ↑ "Brain pyroglutamate amyloid-β is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer's disease therapeutic". Journal of Alzheimer's Disease 41 (1): 129–49. 2014. doi:10.3233/JAD-131370. PMID 24595198. 
  10. ↑ "Coronavirus protein processing and RNA synthesis is inhibited by the cysteine proteinase inhibitor E64d". Virology 208 (1): 1–8. April 1995. doi:10.1006/viro.1995.1123. PMID 11831690. 
  11. ↑ "Host cell cathepsins potentiate Moloney murine leukemia virus infection". Journal of Virology 81 (19): 10506–14. October 2007. doi:10.1128/JVI.02853-06. PMID 17634228. 
  12. ↑ "Advancements in the Development of Anti-SARS-CoV-2 Therapeutics". International Journal of Molecular Sciences 25 (19). October 2024. doi:10.3390/ijms251910820. PMID 39409149. 
  13. ↑ "Repurposing existing drugs for the treatment of COVID-19/SARS-CoV-2 infection: A review describing drug mechanisms of action". Biochemical Pharmacology 183. January 2021. doi:10.1016/j.bcp.2020.114296. PMID 33191206. "In addition, aloxistatin reduces cellular entry of SARS-CoV-2 by 92.3% since cathepsin L is a necessary factor for SARS-CoV-2 cell entry.". 
  14. ↑ "Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV". Nature Communications 11 (1). March 2020. doi:10.1038/s41467-020-15562-9. PMID 32221306. Bibcode: 2020NatCo..11.1620O. "E64D treatment of 293/hACE2 cells reduced entry of SARS-CoV-2 S pseudovirions by 92.5%, indicating that at least one of cathepsins or calpain might be required for SARS-CoV-2 entry.". 




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