Varespladib

Varespladib is an inhibitor of the IIa, V, and X isoforms of secretory phospholipase A2 (sPLA2).[1][2][3] The molecule acts as an anti-inflammatory agent by disrupting the first step of the arachidonic acid pathway of inflammation.[4] From 2006 to 2012, varespladib was under active investigation by Anthera Pharmaceuticals as a potential therapy for several inflammatory diseases, including acute coronary syndrome and acute chest syndrome.[5][6] The trial was halted in March 2012 due to inadequate efficacy.[7] The selective sPLA2 inhibitor varespladib (IC50 value 0.009 µM in chromogenic assay, mole fraction 7.3X10-6)[8] was studied in the VISTA-16 randomized clinical trial (clinicaltrials.gov Identifier: NCT01130246) and the results were published in 2014.[8] The sPLA2 inhibition by varespladib in this setting seemed to be potentially harmful, and thus not  a useful strategy for reducing adverse cardiovascular outcomes from acute coronary syndrome. Since 2016, scientific research has focused on the use of Varespladib as an inhibitor of snake venom toxins[9][10][11][12][13] using various types of  in vitro and in vivo models. Varespladib showed a significant inhibitory effect to snake venom PLA₂ which makes it a potential first-line drug candidate in snakebite envenomation therapy.  In 2019, the U.S. Food and Drug Administration (FDA) granted varespladib orphan drug status for its potential to treat snakebite.

Varespladib
Clinical data
Pregnancy
category
  • —
ATC code
  • none
Legal status
Legal status
  • investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC21H20N2O5
Molar mass380.400 g·mol−1
3D model (JSmol)
 NY (what is this?)

Oral varespladib
Main article: varespladib methyl

Intravenous varespladib
Varespladib sodium
Clinical data
Other namesA-001
Pregnancy
category
  • —
Routes of
administration		IV
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC21H19N2NaO5
Molar mass402.4 g/mol g·mol−1
3D model (JSmol)

Varespladib sodium (also known as A-001, previously LY315920 and S-5920) is a sodium salt of varespladib designed for intravenous delivery.[14] It was under evaluation by Anthera Pharmaceuticals as an anti-inflammatory sPLA2 inhibitor for the prevention of acute chest syndrome (ACS), the leading cause of death for patients with sickle-cell disease.[5]

Elevated serum levels of sPLA2 have been observed in sickle-cell patients preceding and during ACS episodes. This profound elevation in sPLA2 levels is not observed in sickle-cell patients at steady-state or during a vaso-occlusive crisis, or in patients with respiratory diseases such as pneumonia.[15][16] A reduction in serum sPLA2 levels, for example through blood transfusion, reduces the risk of an ACS, suggesting that sPLA2 plays an important role in the onset of ACS.[17]

Anthera Pharmaceuticals acquired varespladib sodium from Lilly and Shionogi in 2006.[5] In 2007, the U.S. Food and Drug Administration (FDA) granted varespladib sodium orphan drug status for its potential to treat patients with sickle-cell disease, which was later withdrawn.[18] In 2009, Anthera Pharmaceuticals completed a Phase II study of varespladib sodium in subjects with sickle cell disease at risk for ACS.[19]

Inhibitory effect on snake venoms

Snakebite envenomation can cause local tissue damage, with edema, hemorrhage, myonecrosis, and systemic toxic responses, including organ failure. In an early report on inhibition of snake venom toxicities, Varespladib, and its orally bioavailable prodrug methyl-varespladib (LY333013) showed strong inhibition of 28 types of svPLA2s from six continents.[13] Varespladib treatment exerted a significant inhibitory effect on snake venom PLA₂ both in vitro and in vivo. Hemorrhage and myonecrosis initiated by D. acuts, A. halys, N. atra, and B. multicinctus in an animal model were significantly reversed by varespladib. Furthermore, edema in gastrocnemius muscle was also attenuated.[12] The sPLA2 inhibitor, LY315920 (varespladib sodium), and its orally bioavailable prodrug, LY333013 (varespladib methyl) were highly effective in preventing lethality following experimental envenoming by M. fulvius in a porcine animal model.[10]

Considering that some of the toxins of snake venoms are enzymes, the search for low molecular weight enzyme inhibitors that could be safely administered immediately after a snakebite re-focused scientists' attention on Varespladib. Its ability to neutralize the enzymatic and toxic activities of three isolated PLA2 toxins (from medically important snakes found in different region around the world) of structural groups I (pseudexin) and II (crotoxin B and myotoxin I) was evaluated. The results obtained showed that Varespladib was able to neutralize the in vitro cytotoxic and in vivo myotoxic activities of purified PLA2s of both the structural group I (pseudexin) and II (myotoxin-I and crotoxin B), however further detailed analysis are needed.[11] Varespladib also effectively inhibited the non-enzymatic myotoxic activity of the snake venom PLA2-like protein (MjTX-II). Co-crystallization of Varespladib with MjTX-II toxin revealed that the compound binds to a hydrophobic channel of the protein. Such interaction blocks fatty acids binding, thus inhibiting allosteric activation of the toxin. This leads to the toxin losing its ability to disrupt cell membranes. [9]

In 2019, the U.S. Food and Drug Administration (FDA) granted varespladib orphan drug status for its potential to treat snakebite.[20]

References
  1. "Following Encouraging Results, Anthera to Continue IMACTS Trial for the Prevention of Acute Chest Syndrome in Patients with Sickle Cell Disease" (Press release). Anthera Pharmaceuticals, Inc. 24 March 2009.
  2. "A-002: Short Term (16 week) Treatment of Acute Coronary Syndrome". Anthera Pharmaceuticals. Retrieved 6 September 2011.
  3. "Varespladib". American Journal of Cardiovascular Drugs. 11 (2): 137–43. April 2011. doi:10.2165/11533650-000000000-00000. PMID 21446779.
  4. Baynes JW, Dominiczak MH (2005). Medical Biochemistry (2 ed.). Elsevier Mosby. pp. 555. ISBN 0-7234-3341-0.
  5. "Anthera Licenses Portfolio of Anti-Inflammatory Products From Eli Lilly and Company and Shionogi & Co., Ltd" (Press release). Anthera Pharmaceuticals, Inc. 6 September 2006.
  6. "Science: sPLA2". Anthera Pharmaceuticals. Retrieved 6 August 2011.
  7. Clinical trial number NCT01130246 for "VISTA-16 Trial: Evaluation of Safety and Efficacy of Short-term A-002 Treatment in Subjects With Acute Coronary Syndrome" at ClinicalTrials.gov
  8. Nicholls SJ, Kastelein JJ, Schwartz GG, Bash D, Rosenson RS, Cavender MA, et al. (January 2014). "Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial". JAMA. 311 (3): 252–62. doi:10.1001/jama.2013.282836. PMID 24247616.
  9. Salvador GH, Gomes AA, Bryan-Quirós W, Fernández J, Lewin MR, Gutiérrez JM, et al. (November 2019). "2-like toxin inhibition by the synthetic compound Varespladib (LY315920)". Scientific Reports. 9 (1): 17203. doi:10.1038/s41598-019-53755-5. PMC 6868273. PMID 31748642.
  10. Lewin MR, Gilliam LL, Gilliam J, Samuel SP, Bulfone TC, Bickler PE, Gutiérrez JM (November 2018). "Micrurus fulvius (Eastern Coral Snake) Venom". Toxins. 10 (11): 479. doi:10.3390/toxins10110479. PMC 6265968. PMID 30453607.
  11. Bryan-Quirós W, Fernández J, Gutiérrez JM, Lewin MR, Lomonte B (January 2019). "2". Toxicon. 157: 1–7. doi:10.1016/j.toxicon.2018.11.292. PMID 30447275. S2CID 53669789.
  12. Wang Y, Zhang J, Zhang D, Xiao H, Xiong S, Huang C (February 2018). "Exploration of the Inhibitory Potential of Varespladib for Snakebite Envenomation". Molecules. 23 (2): 391. doi:10.3390/molecules23020391. PMC 6017252. PMID 29439513.
  13. Lewin M, Samuel S, Merkel J, Bickler P (August 2016). "Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation". Toxins. 8 (9): 248. doi:10.3390/toxins8090248. PMC 5037474. PMID 27571102.
  14. "A-001: Prevention of Acute Chest Syndrome in Sickle Cell Disease". Anthera Pharmaceuticals. Retrieved 18 August 2011.
  15. Styles LA, Schalkwijk CG, Aarsman AJ, Vichinsky EP, Lubin BH, Kuypers FA (March 1996). "Phospholipase A2 levels in acute chest syndrome of sickle cell disease" (PDF). Blood. 87 (6): 2573–8. doi:10.1182/blood.V87.6.2573.bloodjournal8762573. PMID 8630425.
  16. Styles LA, Aarsman AJ, Vichinsky EP, Kuypers FA (November 2000). "Secretory phospholipase A(2) predicts impending acute chest syndrome in sickle cell disease". Blood. 96 (9): 3276–8. doi:10.1182/blood.V96.9.3276. PMID 11050014.
  17. Bostrom MA, Boyanovsky BB, Jordan CT, Wadsworth MP, Taatjes DJ, de Beer FC, Webb NR (March 2007). "Group v secretory phospholipase A2 promotes atherosclerosis: evidence from genetically altered mice". Arteriosclerosis, Thrombosis, and Vascular Biology. 27 (3): 600–6. doi:10.1161/01.ATV.0000257133.60884.44. PMID 17204667.
  18. "Anthera's A-001 Receives Orphan Drug Status For The Prevention Of Acute Chest Syndrome In Patients With Sickle Cell Disease" (Press release). Anthera Pharmaceuticals, Inc. 18 December 2007.
  19. ClinicalTrials.gov. "IMPACTS Trial: Investigation of the Modulation of Phospholipase in Acute Chest Syndrome". United States National Institute of Health. Retrieved 18 August 2011.
  20. "Search Orphan Drug Designations and Approvals". www.accessdata.fda.gov. Retrieved 2020-05-27.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.