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Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation

View Article: PubMed Central - PubMed

ABSTRACT

Snakebite remains a neglected medical problem of the developing world with up to 125,000 deaths each year despite more than a century of calls to improve snakebite prevention and care. An estimated 75% of fatalities from snakebite occur outside the hospital setting. Because phospholipase A2 (PLA2) activity is an important component of venom toxicity, we sought candidate PLA2 inhibitors by directly testing drugs. Surprisingly, varespladib and its orally bioavailable prodrug, methyl-varespladib showed high-level secretory PLA2 (sPLA2) inhibition at nanomolar and picomolar concentrations against 28 medically important snake venoms from six continents. In vivo proof-of-concept studies with varespladib had striking survival benefit against lethal doses of Micrurus fulvius and Vipera berus venom, and suppressed venom-induced sPLA2 activity in rats challenged with 100% lethal doses of M. fulvius venom. Rapid development and deployment of a broad-spectrum PLA2 inhibitor alone or in combination with other small molecule inhibitors of snake toxins (e.g., metalloproteases) could fill the critical therapeutic gap spanning pre-referral and hospital setting. Lower barriers for clinical testing of safety tested, repurposed small molecule therapeutics are a potentially economical and effective path forward to fill the pre-referral gap in the setting of snakebite.

No MeSH data available.


In vitro dose-response curves for varespladib and its orally bioavailable prodrug methyl-varespladib tested against 20 medically important snake venoms. While demonstrating high degrees of potency against snake venoms, neither varespladib nor methyl-varespladib showed high degrees of potency against bee venom sPLA2 (positive control). N = 1 run unless otherwise specified number of replicates. Error bars signify s.d. a. Agkistrodon brevicaudus blomhoffi, b. Bungarus caeruleus, c. B. fasciatus, d. Crotalus adamanteus, e. Crotalus atrox, f. Crotalus scutulatus, g. Dendroaspis polylepis, h. Echis carinatus, i. Laticauda semifasciata, j. Micrurus fulvius, k. Naja naja atra, l. Naja naja kaouthia, m. Naja naja naja, n. Notechis scutatus scutatus, o. Ophiophagus hannah, p. Oxyuranus scutellatus, q. Pseudechis australis, r. Vipera berus, s. Daboia russelli, t. Crotalus durissus terrificus, u. Bee venom (Apis mellifera) purified sPLA2 positive (+) control.
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toxins-08-00248-f001: In vitro dose-response curves for varespladib and its orally bioavailable prodrug methyl-varespladib tested against 20 medically important snake venoms. While demonstrating high degrees of potency against snake venoms, neither varespladib nor methyl-varespladib showed high degrees of potency against bee venom sPLA2 (positive control). N = 1 run unless otherwise specified number of replicates. Error bars signify s.d. a. Agkistrodon brevicaudus blomhoffi, b. Bungarus caeruleus, c. B. fasciatus, d. Crotalus adamanteus, e. Crotalus atrox, f. Crotalus scutulatus, g. Dendroaspis polylepis, h. Echis carinatus, i. Laticauda semifasciata, j. Micrurus fulvius, k. Naja naja atra, l. Naja naja kaouthia, m. Naja naja naja, n. Notechis scutatus scutatus, o. Ophiophagus hannah, p. Oxyuranus scutellatus, q. Pseudechis australis, r. Vipera berus, s. Daboia russelli, t. Crotalus durissus terrificus, u. Bee venom (Apis mellifera) purified sPLA2 positive (+) control.

Mentions: In examining drugs that could be repurposed for snakebite, we found that varespladib (LY315920) and methyl-varespladib (LY333013) inhibited the sPLA2 activity of large arrays of snake venoms in vitro using chromogenic assays, but did not show great activity against bee venom used as a standard, positive control (Table 1 and Figure 1). Additionally surprising was the observation that the IC50 of varespladib and methyl-varespladib for essentially all snake venoms tested was significantly lower than values ever reported for inhibition of mammalian, including human, sPLA2 [32].


Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation
In vitro dose-response curves for varespladib and its orally bioavailable prodrug methyl-varespladib tested against 20 medically important snake venoms. While demonstrating high degrees of potency against snake venoms, neither varespladib nor methyl-varespladib showed high degrees of potency against bee venom sPLA2 (positive control). N = 1 run unless otherwise specified number of replicates. Error bars signify s.d. a. Agkistrodon brevicaudus blomhoffi, b. Bungarus caeruleus, c. B. fasciatus, d. Crotalus adamanteus, e. Crotalus atrox, f. Crotalus scutulatus, g. Dendroaspis polylepis, h. Echis carinatus, i. Laticauda semifasciata, j. Micrurus fulvius, k. Naja naja atra, l. Naja naja kaouthia, m. Naja naja naja, n. Notechis scutatus scutatus, o. Ophiophagus hannah, p. Oxyuranus scutellatus, q. Pseudechis australis, r. Vipera berus, s. Daboia russelli, t. Crotalus durissus terrificus, u. Bee venom (Apis mellifera) purified sPLA2 positive (+) control.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5037474&req=5

toxins-08-00248-f001: In vitro dose-response curves for varespladib and its orally bioavailable prodrug methyl-varespladib tested against 20 medically important snake venoms. While demonstrating high degrees of potency against snake venoms, neither varespladib nor methyl-varespladib showed high degrees of potency against bee venom sPLA2 (positive control). N = 1 run unless otherwise specified number of replicates. Error bars signify s.d. a. Agkistrodon brevicaudus blomhoffi, b. Bungarus caeruleus, c. B. fasciatus, d. Crotalus adamanteus, e. Crotalus atrox, f. Crotalus scutulatus, g. Dendroaspis polylepis, h. Echis carinatus, i. Laticauda semifasciata, j. Micrurus fulvius, k. Naja naja atra, l. Naja naja kaouthia, m. Naja naja naja, n. Notechis scutatus scutatus, o. Ophiophagus hannah, p. Oxyuranus scutellatus, q. Pseudechis australis, r. Vipera berus, s. Daboia russelli, t. Crotalus durissus terrificus, u. Bee venom (Apis mellifera) purified sPLA2 positive (+) control.
Mentions: In examining drugs that could be repurposed for snakebite, we found that varespladib (LY315920) and methyl-varespladib (LY333013) inhibited the sPLA2 activity of large arrays of snake venoms in vitro using chromogenic assays, but did not show great activity against bee venom used as a standard, positive control (Table 1 and Figure 1). Additionally surprising was the observation that the IC50 of varespladib and methyl-varespladib for essentially all snake venoms tested was significantly lower than values ever reported for inhibition of mammalian, including human, sPLA2 [32].

View Article: PubMed Central - PubMed

ABSTRACT

Snakebite remains a neglected medical problem of the developing world with up to 125,000 deaths each year despite more than a century of calls to improve snakebite prevention and care. An estimated 75% of fatalities from snakebite occur outside the hospital setting. Because phospholipase A2 (PLA2) activity is an important component of venom toxicity, we sought candidate PLA2 inhibitors by directly testing drugs. Surprisingly, varespladib and its orally bioavailable prodrug, methyl-varespladib showed high-level secretory PLA2 (sPLA2) inhibition at nanomolar and picomolar concentrations against 28 medically important snake venoms from six continents. In vivo proof-of-concept studies with varespladib had striking survival benefit against lethal doses of Micrurus fulvius and Vipera berus venom, and suppressed venom-induced sPLA2 activity in rats challenged with 100% lethal doses of M. fulvius venom. Rapid development and deployment of a broad-spectrum PLA2 inhibitor alone or in combination with other small molecule inhibitors of snake toxins (e.g., metalloproteases) could fill the critical therapeutic gap spanning pre-referral and hospital setting. Lower barriers for clinical testing of safety tested, repurposed small molecule therapeutics are a potentially economical and effective path forward to fill the pre-referral gap in the setting of snakebite.

No MeSH data available.