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Aloxistatin

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Aloxistatin
Clinical data
ATC code
  • none
Legal status
Legal status
  • US: Investigational drug
Identifiers
  • ethyl (2S,3S)-3-[[(2S)-4-methyl-1-(3-methylbutylamino)-1-oxopentan-2-yl]carbamoyl]oxirane-2-carboxylate
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.163.683 Edit this at Wikidata
Chemical and physical data
FormulaC17H30N2O5
Molar mass342.436 g·mol−1
3D model (JSmol)
  • CCOC(=O)[C@@H]1[C@H](O1)C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C
  • InChI=1S/C17H30N2O5/c1-6-23-17(22)14-13(24-14)16(21)19-12(9-11(4)5)15(20)18-8-7-10(2)3/h10-14H,6-9H2,1-5H3,(H,18,20)(H,19,21)/t12-,13-,14-/m0/s1
  • Key:SRVFFFJZQVENJC-IHRRRGAJSA-N

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] 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%.[12][13]

References

[edit]
  1. ^ Tamai M, Matsumoto K, Omura S, Koyama I, Ozawa Y, Hanada K (August 1986). "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. doi:10.1248/bpb1978.9.672. PMID 3023601.
  2. ^ Tamai M, Yokoo C, Murata M, Oguma K, Sota K, Sato E, Kanaoka Y (March 1987). "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. doi:10.1248/cpb.35.1098. PMID 3301019.
  3. ^ Zhang X, Yang X, Wang H, Li S, Guo K, Jiang D, et al. (August 2017). "Design, Synthesis, and Structure-Activity Relationship Study of Epoxysuccinyl-Peptide Derivatives as Cathepsin B Inhibitors". Biological & Pharmaceutical Bulletin. 40 (8): 1240–1246. doi:10.1248/bpb.b17-00075. PMID 28502922.
  4. ^ Satoyoshi E (July 1992). "Therapeutic trials on progressive muscular dystrophy". Internal Medicine. 31 (7): 841–6. doi:10.2169/internalmedicine.31.841. PMID 1450492.
  5. ^ Ray SK, Matzelle DD, Wilford GG, Hogan EL, Banik NL (June 2001). "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. doi:10.1111/j.1749-6632.2001.tb03655.x. PMID 11462799. S2CID 1828204.
  6. ^ Tsubokawa T, Yamaguchi-Okada M, Calvert JW, Solaroglu I, Shimamura N, Yata K, Zhang JH (September 2006). "Neurovascular and neuronal protection by E64d after focal cerebral ischemia in rats". Journal of Neuroscience Research. 84 (4): 832–40. doi:10.1002/jnr.20977. PMID 16802320. S2CID 24194809.
  7. ^ Trinchese F, Fa' M, Liu S, Zhang H, Hidalgo A, Schmidt SD, et al. (August 2008). "Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease". The Journal of Clinical Investigation. 118 (8): 2796–807. doi:10.1172/JCI34254. PMC 2441853. PMID 18596919.
  8. ^ Hook G, Hook V, Kindy M (2011). "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. doi:10.3233/JAD-2011-110101. PMC 4317342. PMID 21613740.
  9. ^ Hook G, Yu J, Toneff T, Kindy M, Hook V (2014). "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. doi:10.3233/JAD-131370. PMC 4059604. PMID 24595198.
  10. ^ Kim JC, Spence RA, Currier PF, Lu X, Denison MR (April 1995). "Coronavirus protein processing and RNA synthesis is inhibited by the cysteine proteinase inhibitor E64d". Virology. 208 (1): 1–8. doi:10.1006/viro.1995.1123. PMC 7131484. PMID 11831690.
  11. ^ Kumar P, Nachagari D, Fields C, Franks J, Albritton LM (October 2007). "Host cell cathepsins potentiate Moloney murine leukemia virus infection". Journal of Virology. 81 (19): 10506–14. doi:10.1128/JVI.02853-06. PMC 2045468. PMID 17634228.
  12. ^ Yousefi H, Mashouri L, Okpechi SC, Alahari N, Alahari SK (January 2021). "Repurposing existing drugs for the treatment of COVID-19/SARS-CoV-2 infection: A review describing drug mechanisms of action". Biochemical Pharmacology. 183: 114296. doi:10.1016/j.bcp.2020.114296. PMC 7581400. 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.
  13. ^ Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, Guo L, Guo R, Chen T, Hu J, Xiang Z, Mu Z, Chen X, Chen J, Hu K, Jin Q, Wang J, Qian Z (March 2020). "Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV". Nature Communications. 11 (1): 1620. Bibcode:2020NatCo..11.1620O. doi:10.1038/s41467-020-15562-9. PMC 7100515. PMID 32221306. 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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