PLA2G1B

引言人类对蛇的迷恋和恐惧可以追溯到远古时代，第一部关于蛇咬伤的科学论文《Brooklyn Medical Papyrus》可以追溯到古埃及。蛇毒毒液的治疗能力使蛇成为药学和医学的象征，葡萄牙波尔图大学Pedro A. Fernandes综述了蛇毒的化学性质及其在药物开发中的应用潜力。背景介绍蛇毒通常由20-100多种成分混合组成，其中大多数（>90%）是肽和蛋白质，主要生物活性包括神经毒性、血液毒性和细胞毒性。毒液的组成具有多样性，这种多样性是一把双刃剑，一方面限制了抗蛇毒血清的可用性和产量，另一方面提供高度特异性和生物活性化合物，为开发新的治疗药物提供许多途径。蛇毒的化学成分我们回顾了过去15年（2007-2021年）与医学相关的两个毒蛇科：Elapidae(眼镜蛇科)和Viperidae（蝰蛇科）的毒蛇组学研究（图1）。毒液化学成分的差异会导致不同的临床表现，眼镜蛇毒主要引起神经毒性、细胞毒性和心脏毒性表现，而蝰蛇毒通常会引起肌肉毒性和血液毒性。图1 Elapidae(眼镜蛇科)和Viperidae（蝰蛇科）的毒液成分研究眼镜蛇毒液主要由7个家族的多肽和蛋白质组成。分泌的磷脂酶A2(PLA2s)和三指毒素(3FTxs)通常是主要成分（表1）。其他的蛇毒金属蛋白酶(SVMPs)、蛇毒丝氨酸蛋白酶(SVSPs)和l-氨基酸氧化酶(LAAOs)，平均占蛇毒毒素的6%。kunitz型肽是丝氨酸蛋白酶抑制剂家族，平均构成眼镜蛇毒液的~5%。蝰蛇毒液主要包括来自9个蛋白质家族毒素（表1）。在大多数物种中，PLA2、SVMP和SVSP毒素平均占整个毒液蛋白质组的70%。其他以较小比例存在的毒素（4-7%）有LAAOs、c型凝集素和c型凝集素样蛋白，以及利钠肽。表1 蛇毒毒素主要家族的特征1.1种间差异每种眼镜蛇毒液中PLA2s和3FTx的比例差异很大，它们加在一起通常约占总毒液蛋白质组的80%。kunitz型肽通常占比<10%。但也不乏不含PLA2s的黑曼巴蛇（多叶蛇）及东部绿曼巴（树蛇）之类的例外。蝰蛇中不同属（图1）和种的蛇毒毒液组成差异也很大。PLA2、SVSP和SVMP酶家族平均代表病毒蛋白质组的70%。c型凝集素和c型凝集素样蛋白、防御素或利钠肽虽然平均存在量较低，但在特定物种中可占毒液蛋白质组的37%。主要的酶促毒素的化学性质2.1分泌磷脂酶A2PLA2酶催化细胞膜磷脂的sn-2酯键的水解，可分为14类，其中IA和IIA组存在于眼镜蛇和蝰蛇毒液中。在进化过程中，蝰蛇的(Lys49)PLA2同源物没有酶活性，但具有高度的肌毒活性(图2b)。一些神经毒性PLA2具有更精细的分子作用机制，可为药物传递提供思路（图2c）。PLA2酶及其非活性同源物具有广泛的序列和结构相似性，两者都能诱导肌毒性，但分子机制不同。图2 三种主要类型的PLA2与其靶标结合2.2蛇毒金属蛋白酶SVMPs根据结构域的数量（1-3）可分为三类(P-I至P-III)，P-III SVMPs是最大、更古老、最复杂的酶，P-II和P-I酶都是通过结构域丢失进化而来的，它们不同程度的发挥出血效应（图3）。眼镜蛇毒液只含有P-III SVMPs，蝰蛇毒液中含有三组的SVMPs。图3 SVMPs及其底物的结构2.3 蛇毒丝氨酸蛋白酶SVSPs主要具有血液毒性，干扰凝血、血纤维蛋白原水平、血压和血小板聚集(图4a，b)，且具有K+通道阻断活性(图4c)。SVSPs具有典型的胰蛋白酶折叠和高度保守的Ser195-His57-Asp102催化三联体（图4）。大多数SVSPs具有丝氨酸蛋白酶的经典反应机制。图4 SVSPs及其底物的结构从蛇毒毒素中提取的药物3.1批准的药物蛇毒具有典型的细胞毒性、神经毒性和血液毒性。细胞毒素的抗癌潜力早已被认识。从蛇毒神经毒素中提取的药物尚未进入市场，血液毒素已经产生了许多FDA和EMA批准的药物。卡托普利。抗高血压药物卡托普利是第一个基于蛇毒生物活性成分的药物。制药公司Squibb开发了以南美美洲矛头蝮 (Bothrops jararaca)毒液成分中缓激肽增强因子(BPFs)多肽(特别是BPP5a和BPP9a)为模板的抗高血压药物(图5a)：卡托普利。替罗非班。替罗非班是一种抗血小板药物，用于治疗急性冠状动脉综合征。它的结构来源于毒素外组织蛋白，这是一种来自锯鳞蝰蛇(Echis carinatus)毒液的49个残基的分解素(图5b)。依替巴肽。依替巴肽是FDA批准的另一种抗血小板药物，它来源于Barbour响尾蛇(Sistrurus miliarius barbourin)。Barbourin蛋白通过赖氨酸-Gly-Asp(KGD)基序与αIIBβ3整合素结合(图5c)。图5 批准的蛇毒药物除了FDA和EMA批准的药物外，其他蛇毒毒素已在其他国家被批准用于临床使用，描述如下。巴曲酶（去纤维酶）是一种凝血酶样丝氨酸蛋白酶，从巴西刺针蝰蛇(Bothrops moojeni)毒液中纯化的丝氨酸蛋白酶。该毒素在中国和日本上市，用于治疗急性脑梗死、血管闭塞性疾病引起的缺血以及外周和微循环功能障碍。血液凝固酶（蛇毒凝血酶）是一种从普通的刺头坑蝰蛇(Bothrops atrox)的毒液中纯化的酶系统，包括巴曲索酶和一个激活因子X的SVMP，从而发挥抗出血活性，在日本、印度和韩国被批准用于治疗内外出血。α-眼镜蛇毒素是从中国眼镜蛇(Najaatra)的毒液中纯化出来的，是一种3FTxα-神经毒素，在中国被批准用于治疗中度至重度疼痛的镇痛药。3.2在临床前和临床试验中使用的药物安非巴肽是一种抗凝血剂c型凝集素样蛋白，从尖鼻蝰蛇(Deinagkistrodon acutus)的毒液中纯化出来(图6a)。到目前为止，安非巴肽已经通过了I期临床试验。响尾蛇胺是一种小的防御素，是从南美新热带响尾蛇(Crotalus durissus)的毒液中纯化出来的(图6b)。主要的细胞毒性机制是溶酶体的积累和破坏，是一种很有前途的抗肿瘤药物。蛇毒肽是从东部绿曼巴(Dendroaspis angusticeps)毒液中纯化的利钠肽，目前正在进行用于治疗心力衰竭的临床试验(图6c)。曼巴毒蛇肽-1和曼巴毒蛇肽-2是从黑色曼巴蛇毒液中纯化的抑制伤害性感受神经元中酸感应离子通道(ASIC)的亚型1a和1b，是一种强效、无毒镇痛药(图6d)。针对SARS-CoV-2病毒的毒素。鉴于蛇毒PLA2s的抗病毒和抗菌活性，从金环蛇 (Banded krait)、草原蝰蛇(Vipera renardi)和尼古拉基蝰蛇(Vipera nikolskii)的毒液中纯化得到PLA2s，对SARS-CoV-2均具有显著的活性和选择性，它们靶向SARS-CoV-2的靶点是病毒木瓜半胱氨酸蛋白酶。图6 在临床或临床前试验中从蛇毒衍生的药物蛇毒药物4.1确定候选药物从蛇毒中开发药物有两种途径：不经修饰地使用毒素；或者毒素模拟。使用未经修饰的蛇毒素并不是很成功，毒素模拟技术，已经成功地从蛇毒中开发药物。4.2管理路线毒素模拟是克服毒素成药现存问题的一种可能方法：揭示靶标活性和特异性的分子决定因素，然后尽可能广泛地用一种可负担得起的合成和口服生物可利用的小合成分子进行模拟。4.3 靶点确定在凝血级联反应中识别血液毒素的靶点已经非常成功；在了解较少和更复杂的人类神经系统中识别神经毒素的靶点具有挑战性。4.4毒素模拟学中的计算化学与实验协同进行，高水平的计算化学有能力推进靶点识别和靶点-毒素结构的确定；它们一起可以促进使用未经修饰的毒素或基于毒素的小配体的建模。结论蛇毒是一个非凡的生物活性化合物库，具有巨大的药用潜力。综述对构成蛇毒的毒素混合物进行了研究，重点研究了大多数生物活性毒素的分子结构、化学反应性和靶标识别，从中可以开发出生物活性药物。阐述了蛇毒衍生药物的设计和工作机制，并分析了毒素转化为治疗药物的策略。最后，讨论了为实现蛇毒具有巨大的治疗潜力所面临的挑战，并提出了从蛇毒中提取大量新药的化学策略。作者希望这篇综述将激励新一代的科学家去探索和实现蛇毒的巨大潜力。参考文献：Oliveira AL, Viegas MF, da Silva SL, Soares AM, Ramos MJ, Fernandes PA. The chemistry of snake venom and its medicinal potential. Nat Rev Chem. 2022 Jun 10;6(7):1-19. doi: 10.1038/s41570-022-00393-7.封面图来源：http://www.xinhuanet.com/science/2020-11/18/c_139524867.htm识别微信二维码，添加生物制品圈小编，符合条件者即可加入微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

In an industry where proprietary platforms and licenses rule, these companies are choosing collaboration. These new biotech and biopharma agreements involve companies sharing their strengths to develop new treatments for diseases with high unmet need. SciNeuro Pharma and GSK SciNeuro Pharmaceuticals, which develops treatments for neurodegenerative and central nervous system (CNS) diseases, announced an exclusive, worldwide license and option agreement with GlaxoSmithKline (GSK) to research treatment for Alzheimer’s disease. The companies will work together on researching inhibitors of Lp-PLA2, an enzyme associated with neurodegenerative diseases. GSK has already developed some possible inhibitors for Lp-PLA2, and under this agreement, SciNeuro will receive a worldwide license to intellectual property covering certain GSK Lp-PLA2 inhibitors. SciNeuro will pay an upfront fee, near-term and downstream milestones and royalties to GSK as it develops the inhibitors through clinical proof-of-concept. GSK has the option to reclaim rights to the compounds in all territories excluding Greater China, which SciNeuro would retain, under pre-agreed terms for subsequent development and commercialization. If GSK exercises its option, SciNeuro will receive an option exercise fee, downstream milestones and royalty payments from GSK. GSK will also have a right to purchase equity in SciNeuro. vTv Therapeutics and G42 Investments Clinical-stage oral small-molecule developer vTv Therapeutics has entered into an agreement with G42 Investments AI Holding RSC Ltd. In addition to an investment of $25 million, G42 Investments acquired more than 10 million shares of vTv Class A Common Stock at $2.407 per share. $12.5 million was paid in cash to vTv at closing, and the rest of the sum will be payable on May 31, 2023. The funding will support vTv and an affiliate of G42 through Phase III clinical trials of TTP399, a liver selective glucokinase activator, as a treatment for type 1 diabetes. The agreement also includes vTv granting G42’s affiliate an exclusive license to develop and commercialize TTP399 pharmaceutical products in areas outside the U.S. and EU. Another $30 million worth of potential issuance of Class A Common Stock to G42 Investments is also part of the agreement if the U.S. Food and Drug Administration approves the marketing and sale of TTP399. The deal comes three months after Deepa Prasad resigned as CEO at vTv after only four months. During her time as CEO, Prasad streamlined company operations to focus on TTP399. She temporarily remains an advisor to the acting CEO, Rich Nelson, to help guide the company’s direction. Astellas Pharma and GO Therapeutics Astellas Pharma has entered into a strategic research collaboration and license agreement with GO Therapeutics. In the agreement, Xyphos Biosciences Inc., a wholly-owned subsidiary of Astellas, will work with GO to develop novel immuno-oncology therapeutics. "The combination of GO's targets and antibodies and Astellas' ACCEL technology promises to create a new generation of cancer treatments that have a greater therapeutic index. This will enable oncologists to increase the efficacy of antibody-based immunotherapies for solid tumors with less damage to healthy tissues," Constantine Theodoropulos, co-founder and CEO of GO Therapeutics, said in a statement. The companies will collaborate and identify novel antibodies that have a high affinity for certain glycoprotein targets. GO will lead the discovery of the antibodies, and Astellas will lead research, clinical development and commercialization of the therapeutics that GO develops. The agreement states that Xyphos will pay GO an upfront $20.5 million in cash. Another $763 million is on the table, pending the achievement of milestones and contingency payments.

SHANGHAI and ROCKVILLE, Md., June 1, 2022 /PRNewswire/ -- SciNeuro Pharmaceuticals (SciNeuro), a leader in the discovery and development of innovative therapeutics for the treatment of CNS diseases, today announced the execution of an exclusive, worldwide license and option agreement with GlaxoSmithKline (GSK). The agreement focuses on inhibitors of Lp-PLA2, an enzyme that has been implicated in the pathogenesis of neurodegenerative diseases. Clinical findings suggest that inhibition of Lp-PLA2 activity may improve cognitive function in subjects with Alzheimer's disease.1 Under the agreement, SciNeuro will receive a worldwide license to intellectual property covering certain GSK Lp-PLA2 inhibitors and will be responsible for their further development through clinical proof-of-concept (PoC). Following the completion of the PoC studies, GSK has the option to reclaim rights to the compounds in all territories excluding Greater China, which SciNeuro would retain, under pre-agreed terms for subsequent development and commercialization. SciNeuro will pay an upfront fee, near-term and downstream milestones, and royalties to GSK. If GSK exercises its option, SciNeuro will receive an option exercise fee, downstream milestones, and royalty payments from GSK. In addition, GSK will have a right to purchase equity in SciNeuro. "We are excited to further the development of these novel Lp-PLA2 inhibitors. Given the critical role of Lp-PLA2 in CNS integrity and the demonstrated human pharmacology of Lp-PLA2 inhibition, we look forward to evaluating the clinical benefit of these Lp-PLA2 inhibitors in the treatment of CNS diseases," said Min Li, Ph.D., Founder and CEO of SciNeuro Pharmaceuticals. "We are pleased to enter into this agreement with SciNeuro that allows us to assess the clinical potential of these Lp-PLA2 inhibitors by leveraging SciNeuro's early development expertise in CNS disease," said John Lepore, M.D., SVP and Head of Research, at GSK. "This agreement enables us to focus on progressing our own internal assets, while maintaining pipeline optionality for the development of these Lp-PLA2 inhibitors in the future." About SciNeuro Pharmaceuticals SciNeuro Pharmaceuticals is an innovation-driven, neuroscience-focused biopharmaceutical company with an established pipeline of novel therapeutic candidates to address neurodegenerative and other CNS diseases. The company focuses on targets that are supported by human biology and which play a critical role in regulating foundation biology, to achieve better probability of success in clinical development. SciNeuro is committed to delivering medicines that can make a difference to improve the lives of patients around the world, transforming scientific discoveries into groundbreaking therapies. To learn more, visit . SciNeuro Media Contact: Jessie Yang, jessie.yang@scineuro.com 1 Maher-Edwards G, De'Ath J, Barnett C, Lavrov A, Lockhart A. A 24-week study to evaluate the effect of rilapladib on cognition and cerebrospinal fluid biomarkers of Alzheimer's disease. Alzheimers Dement (N Y). 2015;1(2):131-140.