Aloxistatin

Last updated
Aloxistatin
Aloxistatin.svg
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 InfoCard 100.163.683 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H30N2O5
Molar mass 342.436 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] [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. 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. Huang J, Ma Q, Su Z, Cheng X (October 2024). "Advancements in the Development of Anti-SARS-CoV-2 Therapeutics". International Journal of Molecular Sciences. 25 (19): 10820. doi: 10.3390/ijms251910820 . PMC   11477007 . PMID   39409149.
  13. 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.
  14. 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.