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] 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]

Related Research Articles

In biology and biochemistry, protease inhibitors, or antiproteases, are molecules that inhibit the function of proteases. Many naturally occurring protease inhibitors are proteins.

<span class="mw-page-title-main">Serpin</span> Superfamily of proteins with similar structures and diverse functions

Serpins are a superfamily of proteins with similar structures that were first identified for their protease inhibition activity and are found in all kingdoms of life. The acronym serpin was originally coined because the first serpins to be identified act on chymotrypsin-like serine proteases. They are notable for their unusual mechanism of action, in which they irreversibly inhibit their target protease by undergoing a large conformational change to disrupt the target's active site. This contrasts with the more common competitive mechanism for protease inhibitors that bind to and block access to the protease active site.

<span class="mw-page-title-main">Cathepsin</span> Family of proteases

Cathepsins are proteases found in all animals as well as other organisms. There are approximately a dozen members of this family, which are distinguished by their structure, catalytic mechanism, and which proteins they cleave. Most of the members become activated at the low pH found in lysosomes. Thus, the activity of this family lies almost entirely within those organelles. There are, however, exceptions such as cathepsin K, which works extracellularly after secretion by osteoclasts in bone resorption. Cathepsins have a vital role in mammalian cellular turnover.

<span class="mw-page-title-main">Calpain</span> Protease enzyme present in mammals and other organisms

A calpain is a protein belonging to the family of calcium-dependent, non-lysosomal cysteine proteases expressed ubiquitously in mammals and many other organisms. Calpains constitute the C2 family of protease clan CA in the MEROPS database. The calpain proteolytic system includes the calpain proteases, the small regulatory subunit CAPNS1, also known as CAPN4, and the endogenous calpain-specific inhibitor, calpastatin.

<span class="mw-page-title-main">Cathepsin S</span> Protein-coding gene in the species Homo sapiens

Cathepsin S is a protein that in humans is encoded by the CTSS gene. Transcript variants utilizing alternative polyadenylation signals exist for this gene.

<span class="mw-page-title-main">Cathepsin K</span> Protein-coding gene in the species Homo sapiens

Cathepsin K, abbreviated CTSK, is an enzyme that in humans is encoded by the CTSK gene.

<span class="mw-page-title-main">Cathepsin B</span> Protein-coding gene in the species Homo sapiens

Cathepsin B belongs to a family of lysosomal cysteine proteases known as the cysteine cathepsins and plays an important role in intracellular proteolysis. In humans, cathepsin B is encoded by the CTSB gene. Cathepsin B is upregulated in certain cancers, in pre-malignant lesions, and in various other pathological conditions.

<span class="mw-page-title-main">Cathepsin D</span> Protein-coding gene in the species Homo sapiens

Cathepsin D is a protein that in humans is encoded by the CTSD gene. This gene encodes a lysosomal aspartyl protease composed of a protein dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. Cathepsin D is an aspartic endo-protease that is ubiquitously distributed in lysosomes. The main function of cathepsin D is to degrade proteins and activate precursors of bioactive proteins in pre-lysosomal compartments. This proteinase, which is a member of the peptidase A1 family, has a specificity similar to but narrower than that of pepsin A. Transcription of the CTSD gene is initiated from several sites, including one that is a start site for an estrogen-regulated transcript. Mutations in this gene are involved in the pathogenesis of several diseases, including breast cancer and possibly Alzheimer disease. Homozygous deletion of the CTSD gene leads to early lethality in the postnatal phase. Deficiency of CTSD gene has been reported an underlying cause of neuronal ceroid lipofuscinosis (NCL).

<span class="mw-page-title-main">Cathepsin L1</span> Protein-coding gene in the species Homo sapiens

Cathepsin L1 is a protein that in humans is encoded by the CTSL1 gene. The protein is a cysteine cathepsin, a lysosomal cysteine protease that plays a major role in intracellular protein catabolism.

<span class="mw-page-title-main">Cystatin A</span> Protein-coding gene in the species Homo sapiens

Cystatin-A is a protein that in humans is encoded by the CSTA gene.

<span class="mw-page-title-main">Cystatin B</span> Protein-coding gene in the species Homo sapiens

Cystatin-B is a protein that in humans is encoded by the CSTB gene.

<span class="mw-page-title-main">TMPRSS2</span> Protein-coding gene in the species Homo sapiens

Transmembrane protease, serine 2 is an enzyme that in humans is encoded by the TMPRSS2 gene. It belongs to the TMPRSS family of proteins, whose members are transmembrane proteins which have a serine protease activity. The TMPRSS2 protein is found in high concentration in the cell membranes of epithelial cells of the lung and of the prostate, but also in the heart, liver and gastrointestinal tract.

<span class="mw-page-title-main">Cathepsin Z</span> Protein-coding gene in the species Homo sapiens

Cathepsin Z, also called cathepsin X or cathepsin P, is a protein that in humans is encoded by the CTSZ gene. It is a member of the cysteine cathepsin family of cysteine proteases, which has 11 members. As one of the 11 cathepsins, cathepsin Z contains distinctive features from others. Cathepsin Z has been reported involved in cancer malignancy and inflammation.

<span class="mw-page-title-main">Cathepsin L2</span> Protein-coding gene in the species Homo sapiens

Cathepsin L2 is a protein encoded in humans by the CTSV gene.

<span class="mw-page-title-main">Cathepsin W</span> Protein-coding gene in the species Homo sapiens

Cathepsin W is a protein that in humans is encoded by the CTSW gene.

Myeloid and erythroid nuclear termination stage-specific protein (MENT) is a member of the serpin family of protease inhibitors, and participates in DNA and chromatin condensation. Alongside its ability to condense chromatin, MENT is also an effective inhibitor of the proteases cathepsin K, cathepsin L, and cathepsin V, all of which are cysteine proteases. As such, although MENT is structurally classified as a member of the serpin family, it is functionally termed a "cross-class inhibitor," as it is a cysteine rather than a serine protease inhibitor.

<span class="mw-page-title-main">E-64</span> Chemical compound

E-64 is an epoxide which can irreversibly inhibit a wide range of cysteine peptidases.

<span class="mw-page-title-main">3C-like protease</span> Class of enzymes

The 3C-like protease (3CLpro) or main protease (Mpro), formally known as C30 endopeptidase or 3-chymotrypsin-like protease, is the main protease found in coronaviruses. It cleaves the coronavirus polyprotein at eleven conserved sites. It is a cysteine protease and a member of the PA clan of proteases. It has a cysteine-histidine catalytic dyad at its active site and cleaves a Gln–(Ser/Ala/Gly) peptide bond.

<span class="mw-page-title-main">Papain-like protease</span> Protein family of cysteine protease enzymes

Papain-like proteases are a large protein family of cysteine protease enzymes that share structural and enzymatic properties with the group's namesake member, papain. They are found in all domains of life. In animals, the group is often known as cysteine cathepsins or, in older literature, lysosomal peptidases. In the MEROPS protease enzyme classification system, papain-like proteases form Clan CA. Papain-like proteases share a common catalytic dyad active site featuring a cysteine amino acid residue that acts as a nucleophile.

<span class="mw-page-title-main">Gallinamide A</span> Chemical compound

Gallinamide A is potent and selective inhibitor of the human cysteine protease Cathepsin L1 that was first used as a moderate antimalarial agent. Gallinamide A is produced by marine cyanobacteria from Schizothrix species and Symploca sp. which have also shown to have possible anticancer agent, infectious diseases like leishmaniasis, trypanosomiasis and possible uses in Alzheimer's disease, among others.

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. 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. 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.