Venoms as a source for therapeutics:translating venom peptides into analgesics

【作者】 刘中华；

【Author】 Zhonghua Liu;College of Life Sciences,Hunan Normal University;

【机构】 湖南师范大学生命科学院多肽药物湖南省工程实验室； 中国毒理学会生物毒素毒理专业委员会； 中国毒理学会青年委员会；

【摘要】 A greatly diverse range of animals,including arachnids,centipedes,cone snails,reptiles,squid,and wasps,have evolved venoms for the purpose of predation or defense.The use of animal venoms for therapeutic purposes has been well established in Chinese,Indian,Greek and Middle Eastern cultures for millennia.Animal venoms are complex cocktails composed of a great diversity of bioactive compounds including proteins,peptides,organic molecules and salts.Studies indicate that animal venoms also bear a great diversity of bioactivities,which is beneficial for the discovery of new substances of pharmacological interest.There are currently six FDA-approved drugs derived from venom peptides or proteins,with a further ten in clinical trials and many more in various stages of preclinical development.Pain afflicts a fifth of the population;there is an urgent need for new analgesic drugs with minimal side effects.Voltage-gated sodium channels(VGSCs)are essential for the initiation and propagation of action potentials in excitable tissues.Considerable in vivo and in vitro studies indicate that VGSCs play a key role in neuropathic and inflammatory pain.Of the nine subtypes of VGSCs identified to date and designated as Navl.1-1.9,Navl.3,1.7,1.8 and 1.9 play specialized roles in nociceptive pathways and are considered ideal targets for the development of analgesic drugs.We identified two venom peptides from spider and snake venoms,respectively.They could specifically inhibit Navl.7 and Navl.8,respectively.Significantly,nanomolar application of both peptides by intramuscular injection could extenuate inflammatory pain on formalin test,abdominal constriction(writhing)test and the spinal nerve model,respectively.The analgesic effects would compare favorably with that of morphine and didn’t associate with obvious side effects even at20-folder higher dose.Therefore,both peptides might be useful candidates for the development of analgesics.更多还原

【Abstract】 A greatly diverse range of animals,including arachnids,centipedes,cone snails,reptiles,squid,and wasps,have evolved venoms for the purpose of predation or defense.The use of animal venoms for therapeutic purposes has been well established in Chinese,Indian,Greek and Middle Eastern cultures for millennia.Animal venoms are complex cocktails composed of a great diversity of bioactive compounds including proteins,peptides,organic molecules and salts.Studies indicate that animal venoms also bear a great diversity of bioactivities,which is beneficial for the discovery of new substances of pharmacological interest.There are currently six FDA-approved drugs derived from venom peptides or proteins,with a further ten in clinical trials and many more in various stages of preclinical development.Pain afflicts a fifth of the population;there is an urgent need for new analgesic drugs with minimal side effects.Voltage-gated sodium channels(VGSCs) are essential for the initiation and propagation of action potentials in excitable tissues.Considerable in vivo and in vitro studies indicate that VGSCs play a key role in neuropathic and inflammatory pain.Of the nine subtypes of VGSCs identified to date and designated as Nav1.1-1.9,Nav1.3,1.7,1.8 and 1.9 play specialized roles in nociceptive pathways and are considered ideal targets for the development of analgesic drugs.We identified two venom peptides from spider and snake venoms,respectively.They could specifically inhibit Nav1.7 and Nav1.8,respectively.Significantly,nanomolar application of both peptides by intramuscular injection could extenuate inflammatory pain on formalin test,abdominal constriction(writhing) test and the spinal nerve model,respectively.The analgesic effects would compare favorably with that of morphine and didn’t associate with obvious side effects even at20-folder higher dose.Therefore,both peptides might be useful candidates for the development of analgesics.更多还原