CN117098526A - 包含外源性活化环的梭菌神经毒素 - Google Patents
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Abstract
本发明涉及用于将单链梭菌神经毒素通过蛋白水解加工成相应的双链梭菌神经毒素的方法，该方法包括：提供单链梭菌神经毒素；以及使单链梭菌神经毒素与弗林蛋白酶接触；其中单链梭菌神经毒素具有包含多肽序列Arg‑Xaa‑Xaa‑Arg或由多肽序列Arg‑Xaa‑Xaa‑Arg组成的活化环；和其中弗林蛋白酶水解活化环的肽键，由此产生双链梭菌神经毒素。本发明还涉及工程化梭菌神经毒素及其制造方法，以及相关的药物组合物、核苷酸序列以及治疗和美容用途。
Description
发明领域
本发明涉及梭菌神经毒素及其活化和使用方法。
发明背景
梭菌属(genus Clostridia)中的细菌产生高毒力和特定的蛋白质毒素，这种毒素毒害其被运送到的神经元和其他细胞。此类梭菌神经毒素的实例包括破伤风梭菌(C.Tetani，TeNT)和肉毒杆菌(C.botulinum，BoNT)血清型A-G和X产生的神经毒素(参见WO2018/009903 A2)，以及巴拉特梭菌(C.Baratii)和丁酸梭菌(C.Butyricum)产生的神经毒素。
在梭菌神经毒素中，已知有一些毒力最强的毒素。举例来说，取决于血清型，肉毒杆菌神经毒素对小鼠具有0.5至5ng/kg的中位致死剂量(LD50)值。破伤风毒素和肉毒杆菌毒素均通过抑制受影响的神经元的功能，特别是抑制神经递质的释放而起作用。肉毒杆菌毒素作用于神经肌接头并抑制周围神经系统的胆碱能传递，而破伤风毒素作用于中枢神经系统。
梭菌神经毒素在梭菌属中表达为单链多肽。每种梭菌神经毒素均具有一条催化轻链，该轻链与一条重链(包含N-末端易位结构域和C-末端受体结合结构域)被称为活化环的暴露区域隔开。在蛋白质成熟过程中，活化环的蛋白水解切割(cleavage)将通过二硫键结合在一起的梭菌神经毒素的轻链和重链分开，从而产生完全活化的双链毒素。
所述活化过程必须在重组毒素生产的标准生产过程中再现。在常规生产方法中，具有明确定义的切割基序的外源性蛋白酶(诸如胰蛋白酶或Lys-C)用于蛋白水解活化单链梭菌神经毒素。然而，对于一些梭菌神经毒素，与Lys-C或胰蛋白酶一起孵育导致单链多肽的部分或不正确切割，导致产生污染的单链和/或无活性的切割/降解产物(例如在BoNT/E的情况下)。例如，对于肉毒神经毒素血清型X(BoNT/X，参见WO 2018/009903 A2)，活化是有问题的，使用胰蛋白酶或Lys-C切割完全降解多肽。因此，目前没有用于梭菌神经毒素活化的通用外源性蛋白酶。这在鉴定新的梭菌神经毒素或产生修饰的(例如嵌合或杂合)神经毒素时特别成问题，其需要筛选多种蛋白酶以确定正确的活化。对于重新靶向的梭菌神经毒素，用于活化的一些标准蛋白酶也可以在外源靶向部分内切割(cleave)，导致不正确加工的蛋白质，对所需细胞类型的靶向降低。为了避免此类脱靶切割，必须鉴定替代的靶向部分(这也许不总是可能的)，或者必须设计靶向部分以去除标准蛋白酶的切割位点，这可能对靶向部分的结构产生负面影响，和/或增加设计和生产成本。
此外，梭菌神经毒素的体外活化与许多缺点相关。存在与外源性蛋白酶(特别是GMP级蛋白酶)的使用及其在梭菌神经毒素活化后的去除相关的成本。对GMP级蛋白酶的单个或有限数量的供应商的依赖也可能在供应/生产链中产生弱点。从活化外源性蛋白酶纯化活化的梭菌神经毒素也可影响生产效率和产率。此外，根据常规生产方法生产活性双链梭菌神经毒素需要严格的安全和控制程序，也增加了生产成本和时间。对于使用活性双链梭菌神经毒素的从业者也需要严格的安全预防措施。
本发明克服了一个或多个上述问题。
发明概述
蛋白酶弗林蛋白酶(furin)在体内的各种组织中表达，包括脑、内分泌组织、肺、肝、胃肠道、肝、肾和膀胱，并且由多种细胞类型表达。弗林蛋白酶表达主要定位于细胞的高尔基体和核质。弗林蛋白酶在紧接Arg-Xaa-Yaa-Arg(其中Xaa和Yaa是任何氨基酸)肽序列(SEQ ID NO:1)的C末端识别并切割，所述序列特别是Arg-Xaa-Lys-Arg(SEQ ID NO:2)、Arg-Xaa-Arg-Arg(SEQ ID NO:3)或Arg-Lys-Lys-Arg(SEQ ID NO:4)。值得注意的是，所有梭菌神经毒素活化环中都不存在这样的弗林蛋白酶切割位点(参见图1)。因此，弗林蛋白酶先前已被排除作为用于活化梭菌神经毒素的蛋白酶。
本发明的发明人首次证明将弗林蛋白酶切割位点插入梭菌神经毒素中允许梭菌神经毒素的体内活化。这是梭菌神经毒素产生、加工和活化以及实际治疗用途方面的范式转变。特别地，在本领域先前已经尝试将外源切割位点引入梭菌神经毒素中的程度上，目标始终是促进梭菌神经毒素的体外生产和加工，然后以双链形式施用梭菌神经毒素。本发明的发明人首先认识到梭菌神经毒素体内活化的潜力，以证明梭菌神经毒素的体内活化是可能的，并且这可以通过插入弗林蛋白酶切割位点来实现。考虑到本领域的共识(例如WO2002/065336，其通过引用并入本文)，这是特别令人惊讶的，本领域的共识是外源切割位点的插入，即使在体外活化的情况下，也可以引起构象变化，后者可能对切割效率具有负面影响，使得通常所优选的是活化环的完整替换，而不是插入外源活化位点。
此外，本发明的发明人不仅已经显示了弗林蛋白酶切割位点的插入是可能的，并且这可以用于在体内活化梭菌神经毒素，而且他们还令人惊讶地显示了弗林蛋白酶活化梭菌神经毒素可以实现与常规活化的梭菌神经毒素相当的效力。
此外，与常规活化的梭菌神经毒素相比，本发明的弗林蛋白酶活化的工程化梭菌神经毒素提供了若干潜在益处，如改善操作者(例如临床医生或处理本发明的弗林蛋白酶活化的工程化神经毒素以施用于患者的其他人，以及参与弗林蛋白酶活化的工程化神经毒素的生产的工作人员)的安全性，和/或减少制造负担/成本。本发明的弗林蛋白酶活化的工程化神经毒素对于患者也具有潜在增加的安全性。特别地，发明人已经证明了用弗林蛋白酶切割位点部分替换肉毒神经毒素血清型A(BoNT/A)的内源性(天然)活化环产生了工程化BoNT/A，其在小鼠体内从单链形式活化为双链形式，并且在小鼠模型中具有与天然BoNT/A(在梭菌属细菌中产生并由细菌内的天然蛋白酶活化)和在施用前在体外已经活化的重组BoNT/A相当的效力。此外，发明人证明了与重组BoNT/A活性双链相比，具有弗林蛋白酶切割位点的工程化BoNT/A在小鼠中潜在地具有更快的起效(如本文实施例中所示)。等效效力与其他示例性性质组合表明弗林蛋白酶活化的工程化BoNT/A的潜在改善的安全性和治疗窗口。此外，发明人还表明了单链BoNT/A1能够引发治疗效果(如本文实施例中使用单链BoNT/A1引发的DAS评分所证明的)。因此，发明人首次证明了单链梭菌神经毒素(诸如具有弗林蛋白酶切割位点的工程化BoNT/A1和单链BoNT/A1)具有治疗潜力，而不需要在施用前活化为双链形式。
因此，本发明提供了工程化梭菌神经毒素，其包含弗林蛋白酶切割位点，其中在所述弗林蛋白酶切割位点处的切割导致产生双链形式的工程化梭菌神经毒素。
弗林蛋白酶切割位点可包含氨基酸序列Arg-Xaa-Xaa-Arg(SEQ ID NO:1)，优选Arg-Xaa-Lys/Arg-Arg(SEQ ID NO:2和3)，甚至更优选Arg-Lys-Lys-Arg(SEQ ID NO:4)，甚至更优选KQKSSNSRKKR(SEQ ID NO:5)。工程化的梭菌神经毒素可以包含外源性活化环，其包含SEQ ID NO:14至22中的任一个或由其组成，优选SEQ ID NO:22。梭菌神经毒素或其部分的内源性活化环可以被弗林蛋白酶切割位点替代。内源神经毒素活化环可以是选自SEQID NO:34至57的一个或多个。
梭菌神经毒素可以选自：(a)肉毒神经毒素(BoNT)血清型A、血清型B、血清型C、血清型D、血清型E、血清型F、血清型G或血清型X，或破伤风神经毒素(TeNT)；或(b)嵌合BoNT或杂合BoNT。工程化梭菌神经毒素可以是单链梭菌神经毒素：(a)由与SEQ ID NO:23具有至少70％序列同一性的核苷酸序列编码；和/或(b)包含与SEQ ID NO:24或SEQ ID NO:70至78中的一项或多项具有至少70％序列同一性的多肽序列。
工程化梭菌神经毒素可以是重新靶向的梭菌神经毒素，其中梭菌神经毒素的内源性HC或HCC被外源性靶向部分(targeting moiety,TM)替代。
本发明还提供了包含弗林蛋白酶切割位点的工程化BoNT/A，其包含与SEQ ID NO:24中的一项或多项具有至少70％序列同一性，优选至少80％，更优选至少90％，甚至更优选至少95％序列同一性的多肽序列。
本发明还提供了一种用于将本发明的工程化梭菌神经毒素(例如工程化BoNT/A)蛋白水解加工成相应的双链梭菌神经毒素(例如工程化BoNT/A)的方法，所述方法包括使工程化梭菌神经毒素(例如工程化BoNT/A)与弗林蛋白酶接触，从而产生双链梭菌神经毒素(例如BoNT/A)。本发明还提供了可通过所述方法获得的双链梭菌神经毒素或BoNT/A。
本发明还提供了编码本发明的工程化梭菌神经毒素或工程化BoNT/A的多核苷酸。本发明还提供了包含本发明的多核苷酸的表达载体，其与启动子可操作地连接。所述多核苷酸或表达载体可以：(a)包含与SEQ ID NO:23具有至少70％序列同一性的核苷酸序列；和/或(b)编码与SEQ ID NO:24或70至78中的一项或多项具有至少70％序列同一性的多肽序列。
本发明还提供了一种生产本发明的工程化梭菌神经毒素或工程化BoNT/A的方法，所述方法包括以下步骤：在细胞中表达本发明的多核苷酸或表达载体，并回收表达的工程化梭菌神经毒素或工程化BoNT/A。所述方法可以进一步包括将多核苷酸或表达载体引入细胞的步骤。
本发明还提供了表达本发明的工程化梭菌神经毒素或工程化BoNT/A的细胞。所述细胞可包含本发明的多核苷酸或表达载体。
本发明还提供了药物组合物，其包含本发明的工程化梭菌神经毒素、工程化BoNT/A、双链梭菌神经毒素或双链BoNT/A，以及药学上可接受的载体、赋形剂、稀释剂、佐剂、推进剂和/或盐。
本发明还提供了本发明的工程化梭菌神经毒素、工程化BoNT/A、双链梭菌神经毒素或双链BoNT/A，或本发明的药物组合物，用于预防或治疗适用肉毒神经毒素疗法的疾病或病症的方法中，其中任选地，所述疾病或病症选自：与不合需要的免疫分泌相关的病症、斜视(strabismus)、眼睑痉挛、斜视(squint)、肌张力障碍(例如痉挛性肌张力障碍、口下颌肌张力障碍，局灶性肌张力异常、迟发性肌张力不良、喉部肌张力障碍和肢体肌张力障碍以及颈颈肌张力障碍)、斜颈(例如痉挛型斜颈)、受益于细胞/肌肉丧失能力(经由SNARE下调或失活)的美容治疗(美容)应用、眼运动的神经肌肉紊乱或病况(如伴行斜视、垂直斜视、侧直肌麻痹、眼球震颤、甲状腺功能异常肌病)、作家痉挛、磨牙症、Wilson病、震颤、抽搐、节段性肌阵挛、痉挛，由于慢性多发性硬化症引起的痉挛、导致膀胱控制异常的痉挛、男性意像(animus)、背部痉挛、抽筋、骨盆提肌综合征(levator pelvic syndrome)、脊柱裂、迟发性运动障碍、帕金森病、口吃、面肌痉挛、眼睑障碍、脑瘫、局灶性痉挛、痉挛性结肠炎、神经源性膀胱、盆底失弛缓综合征(anismus)、肢体僵直(limb spasticity)、抽动、震颤、磨牙症、肛裂、贲门失弛缓症、吞咽困难、流泪、多汗症、唾液过多、胃肠道分泌物过多、肌肉疼痛(如肌肉痉挛引起的疼痛)、头痛(如紧张性头痛或偏头痛)、幻痛(例如，幻肢痛)、眉沟、皮肤皱纹、癌症、子宫疾病、泌尿生殖器病症、泌尿生殖神经系统疾病、膀胱疼痛综合征、间质性膀胱炎、慢性神经源性炎症和平滑肌障碍。
本发明还提供了本发明的工程化梭菌神经毒素、工程化BoNT/A、双链梭菌神经毒素或双链BoNT/A或本发明的药物组合物在制备用于预防或治疗适用肉毒神经毒素疗法的疾病或病症的药物中的用途，其中任选地，所述疾病或病症选自：与不合需要的免疫分泌相关的病症、斜视(strabismus)、眼睑痉挛、斜视(squint)、肌张力障碍(例如痉挛性肌张力障碍、口下颌肌张力障碍，局灶性肌张力异常、迟发性肌张力不良、喉部肌张力障碍和肢体肌张力障碍以及颈颈肌张力障碍)、斜颈(例如痉挛型斜颈)、受益于细胞/肌肉丧失能力(经由SNARE下调或失活)的美容治疗(美容)应用、眼运动的神经肌肉紊乱或病况(如伴行斜视、垂直斜视、侧直肌麻痹、眼球震颤、甲状腺功能异常肌病)、作家痉挛、磨牙症、Wilson病、震颤、抽搐、节段性肌阵挛、痉挛，由于慢性多发性硬化症引起的痉挛、导致膀胱控制异常的痉挛、男性意像(animus)、背部痉挛、抽筋、骨盆提肌综合征(levator pelvic syndrome)、脊柱裂、迟发性运动障碍、帕金森病、口吃、面肌痉挛、眼睑障碍、脑瘫、局灶性痉挛、痉挛性结肠炎、神经源性膀胱、盆底失弛缓综合征(anismus)、肢体僵直(limb spasticity)、抽动、震颤、磨牙症、肛裂、贲门失弛缓症、吞咽困难、流泪、多汗症、唾液过多、胃肠道分泌物过多、肌肉疼痛(如肌肉痉挛引起的疼痛)、头痛(如紧张性头痛或偏头痛)、幻痛(例如，幻肢痛)、眉沟、皮肤皱纹、癌症、子宫疾病、泌尿生殖器病症、泌尿生殖神经系统疾病、膀胱疼痛综合征、间质性膀胱炎、慢性神经源性炎症和平滑肌障碍。
本发明还提供了美容组合物，其包含本发明的工程化梭菌神经毒素、工程化BoNT/A、双链梭菌神经毒素或双链BoNT/A，以及美容上可接受的载体、赋形剂、稀释剂、佐剂、推进剂和/或盐。
本发明还提供了本发明的美容组合物的用途，用于预防或减轻适用应用肉毒神经毒素的美容适应症。
本发明还提供了一种用于将单链梭菌神经毒素蛋白水解加工成相应的双链梭菌神经毒素的方法，所述方法包括：(a)提供单链梭菌神经毒素；和(b)使单链梭菌神经毒素与弗林蛋白酶接触；其中单链梭菌神经毒素具有包含多肽序列Arg-Xaa-Xaa-Arg(SEQ ID NO:1)或由其组成的活化环；并且其中弗林蛋白酶水解所述活化环的肽键，从而产生双链梭菌神经毒素。活化环可包含以下或由以下组成：(a)Arg-Xaa-Lys/Arg-Arg(SEQ ID NO:2或3)；(b)Arg-Lys-Lys-Arg(SEQ ID NO:4)；和/或(c)KQKSSNSRKKR(SEQ ID NO:5)。单链梭菌神经毒素可以：(a)是本发明的工程化梭菌神经毒素；(b)由与SEQ ID NO:23具有至少70％序列同一性的核苷酸序列编码；和/或(c)包含与SEQ ID NO:24或70至78中的一项或多项具有至少70％序列同一性的多肽序列。
本发明还提供了梭菌神经毒素、或包含所述梭菌神经毒素的药物组合物，用于预防或治疗适用肉毒神经毒素疗法的疾病或病症的方法中，其中梭菌神经毒素以单链形式施用于受试者。所述梭菌神经毒素或药物组合物可以基本上不含双链形式的梭菌神经毒素。梭菌神经毒素或药物组合物可包含小于400pg双链梭菌神经毒素/100ng单链梭菌神经毒素，或小于300pg双链梭菌神经毒素/100ng单链梭菌神经毒素，或小于200pg双链梭菌神经毒素/100ng单链梭菌神经毒素，或小于100pg双链梭菌神经毒素/100ng单链梭菌神经毒素，或小于50pg双链梭菌神经毒素/100ng单链梭菌神经毒素。所述疾病或病症可以选自：与不合需要的免疫分泌相关的病症、斜视(strabismus)、眼睑痉挛、斜视(squint)、肌张力障碍(例如痉挛性肌张力障碍、口下颌肌张力障碍，局灶性肌张力异常、迟发性肌张力不良、喉部肌张力障碍和肢体肌张力障碍以及颈颈肌张力障碍)、斜颈(例如痉挛型斜颈)、受益于细胞/肌肉丧失能力(经由SNARE下调或失活)的美容治疗(美容)应用、眼运动的神经肌肉紊乱或病况(如伴行斜视、垂直斜视、侧直肌麻痹、眼球震颤、甲状腺功能异常肌病)、作家痉挛、磨牙症、Wilson病、震颤、抽搐、节段性肌阵挛、痉挛，由于慢性多发性硬化症引起的痉挛、导致膀胱控制异常的痉挛、男性意像(animus)、背部痉挛、抽筋、骨盆提肌综合征(levatorpelvic syndrome)、脊柱裂、迟发性运动障碍、帕金森病、口吃、面肌痉挛、眼睑障碍、脑瘫、局灶性痉挛、痉挛性结肠炎、神经源性膀胱、盆底失弛缓综合征(anismus)、肢体僵直(limbspasticity)、抽动、震颤、磨牙症、肛裂、贲门失弛缓症、吞咽困难、流泪、多汗症、唾液过多、胃肠道分泌物过多、肌肉疼痛(如肌肉痉挛引起的疼痛)、头痛(如紧张性头痛或偏头痛)、幻痛(例如，幻肢痛)、眉沟、皮肤皱纹、癌症、子宫疾病、泌尿生殖器病症、泌尿生殖神经系统疾病、膀胱疼痛综合征、间质性膀胱炎、慢性神经源性炎症和平滑肌障碍。
本发明还提供了包含单链梭菌神经毒素和美容上可接受的载体、赋形剂、稀释剂、佐剂、推进剂和/或盐的美容组合物的用途，用于预防或减轻适用应用肉毒神经毒素的美容适应症，其中单链梭菌神经毒素以单链形式施用于受试者。
附图简述
图1：显示了所有BoNT血清型和破伤风毒素的活化环的蛋白质序列的比较，其中两个侧翼半胱氨酸形成连接毒素分子的轻链和重链的二硫桥。BoNT/C1和BoNT/CD中的因子Xa切割位点(IDGR)用下划线标出。
图2：蛋白质凝胶和蛋白质印迹证实通过弗林蛋白酶成功切割BoNT/A1-弗林蛋白酶蛋白SEQ ID NO:24(SXN104539)。
图3：天然BoNT/A1(方形)、野生型单链rBoNT/A1(菱形)和具有弗林蛋白酶环(furin loop)的单链rBoNT/A1(圆形)在大鼠胚胎脊髓神经元(eSCN)中的SNAP-25切割百分比。将大鼠胚胎脊髓神经元培养三周，并单独用每种BoNT分子处理24h，然后用SNAP-25特异性抗体进行蛋白质印迹。数据是来自一式三份的三个独立实验的平均值±SEM。
图4：小鼠膈神经半膈肌测定(mouse phrenic nerve hemi-diaphragm assay,mPNHD)中野生型双链rBoNT/A1(三角形)、野生型单链rBoNT/A1(加号)和具有弗林蛋白酶环的单链rBoNT/A1(圆形)的效力(t50)。(A)将小鼠膈神经半膈组织与所示的BoNT分子孵育。记录隔膜收缩力直至不再可检测到收缩或140分钟之后。每个点对应于独立的测定。(b)t50值是将小鼠半膈肌收缩力抑制50％所需的时间。
图5：野生型双链rBoNT/A1(方形)、野生型单链rBoNT/A1(菱形)和具有弗林蛋白酶环的单链rBoNT/A1(圆形)在注射到腓肌或腓肠肌外侧肌(gastrocnemius lateralis)后对体重的影响。(A)曲线对应于施用后1、2、3或4天观察到的平均体重。(B)曲线对应于施用后长达25天观察到的平均体重。所有值均为平均值±平均值的标准误差。
图6：注射到腓肌或腓肠肌外侧肌后，野生型双链rBoNT/A1(方形)、野生型单链rBoNT/A1(菱形)和具有弗林蛋白酶环的单链rBoNT/A1(圆形)在平均峰值趾外展评分(digit abduction score,DAS)中的功效。曲线对应于施用后1、2、3或4天观察到的平均峰值DAS响应。所有值均为平均值±平均值的标准误差。
图7：野生型双链rBoNT/A1(方形)、野生型单链rBoNT/A1(菱形)和具有弗林蛋白酶环的单链rBoNT/A1(圆形)在注射到腓肌或腓肠肌外侧肌后对体重的持续时间。曲线对应于施用后长达600小时观察到的平均峰值DAS响应。所有值均为平均值±平均值的标准误差。
发明详述
定义
除非另有定义，否则本文中使用的所有技术和科学术语具有与本公开所属领域的普通技术人员通常所理解的相同含义。Singleton等，DICTIONARY OF MICROBIOLOGY ANDMOLECULAR BIOLOGY，第20版，John Wiley and Sons,New York(1994)，和Hale&Marham，THEHARPER COLLINSDICTIONARY OF BIOLOGY，Harper Perennial，NY(1991)，为技术人员提供了本公开中使用的许多术语的通用词典。术语的含义和范围应该是清楚的；然而，在任何潜在歧义的情况下，本文提供的定义优先于任何字典或外在定义。
应当理解，本发明不限于本文所述的特定方法、方案和试剂等，因此可以变化。特别地，与本文所述的那些类似或等同的任何方法和材料可用于实践或测试本公开的实施方案。
本公开的实施方案的描述并非旨在穷举或将本公开限于所公开的精确形式。虽然出于说明性目的在本文中描述了本公开的具体实施方案和示例，但是如相关领域的技术人员将认识到的，在本公开的范围内的各种等同修改是可能的。例如，虽然以给定顺序呈现方法步骤或功能，但是替代实施方案可以以不同的顺序执行功能，或者可以基本上同时执行功能。本文提供的本公开的教导可以适当地应用于其他程序或方法。可以组合本文所述的各种实施方案以提供另外的实施方案。如果需要，可以修改本公开的方面，以采用上述参考文献和申请的组合物、功能和概念来提供本公开的另外的实施方案。此外，由于生物功能等效性考虑，可以在蛋白质结构中进行一些改变而不影响生物或化学作用的种类或量。根据详细的描述，可以对本公开进行这些和其他改变。所有这些修改旨在包括在所附权利要求的范围内。
除非另有说明，否则分别地，任何核酸序列都以5'至3'的方向从左至右书写；氨基酸序列以氨基至羧基的方向从左至右书写。
本文提供的标题不是对本公开的各个方面或实施方案的限制。
如本文所用，与动词一起使用时，术语“能够”涵盖或意指相应动词的作用，例如，“能够相互作用”也意指相互作用，“能够切割”也意指切割，“能够结合”也意指结合，并且“能够特异性靶向…”也意指特异性靶向。
数值范围包括限定该范围的数字。在提供值的范围的情况下，应理解的是，除非上下文另外明确指出，否则在该范围的上限和下限之间、每个居中值至下限单位的十分之一，具体包括在本公开内。在指定范围内的任何指定值或居中值与该指定范围内的任何其他指定值或居中值之间的每个较小范围都包括在本公开中。这些较小范围的上限和下限可以独立地包括在该范围内或排除在该范围内，并且每个范围也包括在本公开内，其中包括在较小范围内的上下限之一、均不包括、或包括二者，以所述范围内的任何明确排除的限为准。在所述范围包括一个或两个限的情况下，排除那些包括的限中任一个或两个的范围也包括在本公开中。
在本文中，使用氨基酸名称、三字母缩写或单字母缩写来指代氨基酸。如本文所用，术语“蛋白质”包括蛋白质、多肽和肽。如本文所用，术语“氨基酸序列”与术语“多肽”和/或术语“蛋白质”同义。在一些情况下，术语“氨基酸序列”与术语“肽”同义。在一些情况下，术语“氨基酸序列”与术语“酶”同义。术语“蛋白质”和“多肽”在本文可互换使用。在本公开和权利要求中，可以使用氨基酸残基的常规单字母和三字母密码子。根据IUPACIUB生化命名联合委员会(JCBN)定义氨基酸的3个字母密码子。还应理解，由于遗传密码子的简并性，多肽可以被一个以上的核苷酸序列编码。
多肽的“片段”通常包含原始多肽的至少50％、至少60％、至少70％、至少80％、至少90％、至少95％、至少97％或更多。
如本文所用，术语“多核苷酸”、“核酸”和“核酸序列”是指掺入核糖核酸、脱氧核糖核酸或其类似物的单元的任何分子，优选聚合分子。核酸可以是单链或双链的。单链核酸可以是变性双链DNA的一条核酸链。或者，它可以是不衍生自任何双链DNA的单链核酸。在一个方面中，核酸可以是DNA。在另一个方面中，核酸可以是RNA，合适的核酸分子是DNA，包括基因组DNA或cDNA。其他合适的核酸分子是RNA，包括siRNA、shRNA和反义寡核苷酸。
术语“增加的”、“增加”、“增强”或“活化”在本文中均用于意指增加了统计学上显著的量。术语“增加的”、“增加”、“增强”或“活化”可以意指与参照水平相比至少10％的增加，例如与参照水平相比至少约20％、或至少约30％、或至少约40％、或至少约50％、或至少约60％、或至少约70％、或至少约80％、或至少约90％或至多并包括100％的增加或10-100％之间的任何增加，或与参照水平相比至少约2倍、或至少约3倍、或至少约4倍，或至少约5倍或至少约10倍的增加或2倍和10倍或更大之间的任何增加。
术语“减少”、“降低的”、“降低”或“抑制”在本文中均用于意指减少了统计学上显著的量。术语“降低(reduce)”、“降低(reduction)”、“减少”或“抑制”通常意指与参考水平(例如，不存在给定治疗)相比至少10％的减少，并且可以包括例如与参考水平相比至少约10％、至少约20％、至少约25％、至少约30％、至少约35％、至少约40％、至少约45％、至少约50％、至少约55％、至少约60％、至少约65％、至少约70％、至少约75％、至少约80％、至少约85％、至少约90％、至少约95％、至少约98％、至少约99％或更多的减少。如本文所用，“降低”或“抑制”涵盖与参考水平相比的完全抑制或降低。“完全抑制”是与参考水平相比100％抑制(即消除)。
术语的其他定义可以出现在整个说明书中。在更详细地描述示例性实施方案之前，应当理解，本公开不限于所描述的特定实施方案，并且因此可以变化。还应理解，本文使用的术语仅用于描述特定实施方案的目的，并不旨在限制，因为本公开的范围将仅由所附权利要求限定。
必须注意的是，如本文和所附权利要求书中所使用的，单数形式的“一个”，“一种”和“该”包括复数指示物，除非上下文另外明确指出。因此，例如，提及“梭菌神经毒素”包括多种这样的候选试剂，并且提及“梭菌神经毒素”包括提及一种或多种梭菌神经毒素及本领域技术人员已知的其等同物，等等。
此外，术语“包括(including)”以及其他形式如“包括(includes)”和“包括(included)”的使用不是限制性的。
“约”通常可以意指在给定测量的性质或精度的情况下测量的量的可接受的误差程度。示例性误差程度在给定值或值范围的20％内，通常在10％内，更通常在5％内。优选地，术语“约”在本文中应理解为加或减(±)与其一起使用的数字的5％，优选±4％、±3％、±2％、±1％、±0.5％、±0.1％的数值。
术语“由……组成”是指如本文所述的组合物、方法及其相应组分，其不包括该发明描述中未列举的任何要素。
如本文所用，术语“基本上由……组成”是指给定发明所需的那些要素。该术语允许存在不会实质上影响本发明的基本和新的或功能特征的元素(即无活性或非免疫原性成分)。
本文描述为“包含”一个或多个特征的实施方案也可以被认为是“由这些特征组成”和/或“基本上由这些特征组成”的相应实施方案的公开内容。
浓度、量、体积、百分比和其他数值在本文中可以以范围形式呈现。还应当理解，这样的范围格式仅为了方便和简洁而使用，并且应当灵活地解释为不仅包括明确列举为范围界限的数值，而且还包括该范围内涵盖的所有单独的数值或子范围，如同明确列举了每个数值和子范围一样。
个体可以是先前已经被诊断为或被鉴定为患有或具有需要治疗的病症或与这种病症相关的一种或多种并发症，并且任选地，已经经历如本文所定义的病症或与所述病症相关的一种或多种并发症的治疗的个体。或者，个体也可以是先前未曾被诊断为患有如本文所定义的病症或与所述病症相关的一种或多种并发症的个体。例如，个体可以是表现出病症或与所述病症相关的一种或多种并发症的一种或多种风险因素的个体或不表现出风险因素的受试者。
对于特定病症的治疗“有需要的个体”可以是患有该病症、被诊断为患有该病症或处于发展该病症的风险中的个体。
术语“受试者”、“个体”和“患者”在本文中可互换使用，是指哺乳动物个体。“个体”可以是任何哺乳动物。一般来说，个体可以是人；换句话说，在一个实施方案中，“个体”是人。“个体”可以是成人、青少年或婴儿。“个体”可以是男性或女性。
如本文所用的术语“药学上可接受的”意指由联邦或州政府的管理机构批准，或在美国药典、欧洲药典或其他公认的药典中列出。
提供本文所讨论的出版物仅仅是因为它们在本申请的提交日之前的公开内容。本文中的任何内容都不应被解释为承认这些出版物构成所附权利要求的现有技术。
工程化的梭菌神经毒素
本发明提供了工程化梭菌神经毒素，其包含弗林蛋白酶切割位点。通常，在所述弗林蛋白酶切割位点处的切割导致产生双链形式的工程化梭菌神经毒素。换句话说，弗林蛋白酶切割位点处的切割导致工程化梭菌神经毒素的活化。梭菌神经毒素的内源性(天然)活化环可以被弗林蛋白酶切割位点替代(或部分替代)。因此，术语“弗林蛋白酶切割位点”可以与术语“弗林蛋白酶活化位点”互换使用，并且如本文所定义的外源性活化环通常包含弗林蛋白酶切割位点或由其组成。本发明的工程化梭菌神经毒素可以在体内活化。因此，工程化的梭菌神经毒素开辟了梭菌神经毒素的加工和治疗用途的新领域，使得毒素能够作为单链梭菌神经毒素产生和施用，然后将其切割以在体内产生活性双链形式。如本文所述，这代表梭菌神经毒素领域的范式转变。
梭菌神经毒素(工程化前)的特征通常在于内源性活化环被弗林蛋白酶低效地蛋白水解加工。与梭菌神经毒素(工程化前)相反，本发明的工程化梭菌神经毒素不被弗林蛋白酶低效地蛋白水解加工和/或工程化梭菌神经毒素的外源性活化环外部的肽键不被弗林蛋白酶水解。因此，梭菌神经毒素(工程化前)通常对弗林蛋白酶的蛋白水解加工具有抗性。术语“被弗林蛋白酶低效地蛋白水解加工”、“抵抗弗林蛋白酶的蛋白水解加工”、“基本上不被弗林蛋白酶水解”、“被弗林蛋白酶低效地活化”、“抵抗弗林蛋白酶活化”和“基本上不被弗林蛋白酶活化”在本文中可互换使用。
梭菌神经毒素(工程化前)通常是其中肽键(在活化环内或外)不被或基本上不被弗林蛋白酶水解的神经毒素。术语“基本上不被水解”是指在本发明的方法中，反应中存在的梭菌神经毒素少于10％、5％、4％、3％、2％或1％含有已被弗林蛋白酶水解的肽键。
因此，梭菌神经毒素(工程化前)通常在其内源性活化环内不含弗林蛋白酶切割位点(例如，如本文所定义的)。因此，在一些实施方案中，本发明涉及梭菌神经毒素(工程化前)，其不是UniProt登录号AB745660的BoNT/DC(序列的版本1，访问于2022年1月19日)、UniProt登录号P18640的BoNT/C1(序列的版本3，访问于2022年3月23日)、UniProt登录号Q5DW55的BoNT/CD(序列的版本1，访问于2022年3月23日)、NCBI登录号AB012112的BoNT/D(序列的版本1，访问于2022年3月23日)和/或UniProt登录号D2KHQ9的BoNT/F5(序列的版本1，访问于2022年3月23日)。
本发明可包括用(外源)弗林蛋白酶切割位点或包含如本文所述的弗林蛋白酶切割位点的外源性活化环替换任何梭菌神经毒素的内源性活化环(或其部分)。梭菌神经毒素可以是肉毒神经毒素(BoNT)或破伤风神经毒素(TeNT)。优选地，梭菌神经毒素是肉毒神经毒素，如BoNT/A、BoNT/B、BoNT/C1、BoNT/D、BoNT/E、BoNT/F、BoNT/G或BoNT/X，或其嵌合或杂合体。
如本文所用，术语“内源性活化环”是指在受试者梭菌神经毒素中存在的活化环，例如，指定血清型的受试者梭菌神经毒素中存在的活化环。例如，BoNT/A1包括BoNT/A1重链和轻链，因此BoNT/A1的内源性活化环是A1活化环。对于梭菌神经毒素嵌合体或杂合体，本领域技术人员可以例如通过确定衍生L链和HN结构域的血清型来鉴定“内源性活化环”。在一些实施方案中，嵌合体或杂合体梭菌神经毒素可具有内源性活化环，其是来自两种不同血清型的活化环的融合。举例来说，嵌合梭菌神经毒素，例如BoNT/A1C1具有BoNT/A1轻链和易位结构域，因此内源性BoNT/A1C1活化环是A1活化环。图1中提供了活化环的示例。内源性活化环通常由形成二硫桥并共价连接(工程化前)梭菌神经毒素的轻链和重链的半胱氨酸残基界定。因此，内源性活化环序列可以被叙述为包括边界半胱氨酸残基(如本文所述的)或不包括边界半胱氨酸残基。本领域普通技术人员将理解，定义可以互换使用，并且将能够容易地确定内源性活化环，包括或排除边界半胱氨酸残基。
通常，“内源性活化环”是不包含SEQ ID NO:1或不由SEQ ID NO:1组成的任何活化环。优选地，“内源性活化环”为不是SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4和/或SEQ IDNO:5的任何活化环。
相比之下，本文所用的“外源性活化环”是指与受试者梭菌神经毒素(例如指定血清型的受试者梭菌神经毒素)中存在的内源性活化环不同的活化环，并且其中外源性活化环包含弗林蛋白酶切割位点。例如，BoNT/C1活化环与野生型BoNT/A1活化环具有不同的多肽序列，因此BoNT/C1活化环对BoNT/A1是外源性的。对于梭菌神经毒素嵌合体或杂合体，本领域技术人员可以，例如通过确定衍生L链和HN结构域的血清型来确定活化环是否是“外源性活化环”。例如，当L链是BoNT/B L链，并且HN结构域来自BoNT/D时，内源性活化环可具有BoNT/B序列的一部分和BoNT/D序列的一部分，如果活化环(例如C1活化环)与其不同，并且包含弗林蛋白酶切割位点，则被视为“外源性活化环”。
可以通过将受试者梭菌神经毒素的序列与活化环比对，并查看该活化环是否存在于受试者梭菌神经毒素序列中，来确定活化环是否为“内源性活化环”。如果它存在，则活化环可以被鉴定为内源性活化环。如本文所描述，梭菌神经毒素的内源性活化环被作为弗林蛋白酶切割位点的外源切割位点或包含弗林蛋白酶切割位点的外源性活化环替代。
通常，根据本发明，在为工程化前梭菌神经毒素的内源性活化环划界的两个半胱氨酸残基之间插入弗林蛋白酶切割位点，但弗林蛋白酶切割位点在内源性活化环内的精确位置不受限制，条件是所得工程化梭菌神经毒素的构象不被破坏和/或工程化梭菌神经毒素不变得无功能。
整个内源性活化环被弗林蛋白酶切割位点或包含如本文所述的弗林蛋白酶切割位点的外源性活化环替代。或者，可以替换内源性活化环的一部分或部分(在本文中也称为内源性活化环的部分替换)，例如内源性活化环的至少5、10、15、20、25、30、35或40个氨基酸残基被替换。优选内源性活化环的5至20个，更优选5至15个氨基酸残基被替换。通常，部分替换涉及内源性活化环内的连续氨基酸的替换。
内源性活化环的替换可以通过本领域已知的任何方法来实现。例如，可以通过氨基酸修饰来实现替换。可以通过缺失内源性活化环的一个或多个氨基酸残基来替换内源性活化环。可以通过用外源性活化环的氨基酸残基取代内源性活化环的一个或多个氨基酸残基来替换内源性活化环。可以缺失内源性活化环(或其部分)，并且插入弗林蛋白酶切割位点或包含弗林蛋白酶切割位点的外源性活化环，优选地位于形式上被内源性活化环占据的位置。或者，内源性活化环可以保留在本发明的工程化梭菌神经毒素中，并且优选被失活(例如通过突变)。优选内源性活化环(其一部分或整个内源性活化环)不存在于本发明的工程化梭菌神经毒素中。优选弗林蛋白酶切割位点或包含弗林蛋白酶切割位点的外源性活化环占据梭菌神经毒素中形式上被内源性活化环占据的位置。为避免疑义，修饰内源性活化环以包含弗林蛋白酶切割位点时(例如通过取代内源性活化环内的残基或通过添加一个或多个氨基酸以在内源性活化环内形成弗林蛋白酶切割位点)时，修饰的活化环是根据本发明的外源性活化环。因此，潜在地，工程化梭菌神经毒素可以包含其内源性活化/切割位点和弗林蛋白酶切割位点两者，并且因此可以通过天然活化蛋白酶(或重组BoNT生产中使用的等同物，例如胰蛋白酶或Lys-C)或弗林蛋白酶任一者活化。
通过氨基酸残基的取代、插入或缺失来修饰蛋白质的方法是本领域已知的，并且可以用于本发明的实践中。举例来说，可以通过修饰编码梭菌神经毒素的DNA序列来引入氨基酸修饰。这可以使用标准分子克隆技术来实现，例如通过定点诱变，其中编码所需氨基酸的短链DNA(寡核苷酸)用于代替原始编码序列(通过使用聚合酶，或通过用各种酶(例如连接酶和限制性核酸内切酶)插入/缺失基因的一部分)。或者，可以化学合成修饰的基因序列。
根据本发明被替换的内源性活化环可以包含以下或由以下组成：与SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:36、SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39、SEQ IDNO:40、SEQ ID NO:41、SEQ ID NO:42、SEQ ID NO:43、SEQ ID NO:44、SEQ ID NO:45、SEQ IDNO:46、SEQ ID NO:47、SEQ ID NO:48、SEQ ID NO:49、SEQ ID NO:50、SEQ ID NO:51、SEQ IDNO:52、SEQ ID NO:53、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56或SEQ ID NO:57具有至少70％(例如，至少80％或90％)序列同一性的多肽序列。特别地，内源性活化环可以包含以下或由以下组成：与SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:36、SEQ ID NO:37、SEQ IDNO:38、SEQ ID NO:39、SEQ ID NO:40、SEQ ID NO:41、SEQ ID NO:42、SEQ ID NO:43、SEQ IDNO:44、SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48、SEQ ID NO:49、SEQ IDNO:50、SEQ ID NO:51、SEQ ID NO:52、SEQ ID NO:53、SEQ ID NO:54、SEQ ID NO:55、SEQ IDNO:56或SEQ ID NO:57具有至少95％序列同一性的多肽序列。优选地，内源性活化环包含以下或由以下组成：如SEQ ID NO:34、SEQ ID NO:35、SEQ ID NO:36、SEQ ID NO:37、SEQ IDNO:38、SEQ ID NO:39、SEQ ID NO:40、SEQ ID NO:41、SEQ ID NO:42、SEQ ID NO:43、SEQ IDNO:44、SEQ ID NO:45、SEQ ID NO:46、SEQ ID NO:47、SEQ ID NO:48、SEQ ID NO:49、SEQ IDNO:50、SEQ ID NO:51、SEQ ID NO:52、SEQ ID NO:53、SEQ ID NO:51、SEQ ID NO:52、SEQ IDNO:53、SEQ ID NO:54、SEQ ID NO:55、SEQ ID NO:56或SEQ ID NO:57所示的多肽序列。
根据本发明被替换的内源性活化环可包含与SEQ ID NO:37、SEQ ID NO:38、SEQID NO:39、SEQ ID NO:40或SEQ ID NO:41具有至少70％(例如至少80％或90％)序列同一性的多肽序列或由其组成。内源性活化环可包含与SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39、SEQ ID NO:40或SEQ ID NO:41具有至少95％序列同一性的多肽序列或由其组成。优选地，内源性活化环包含如SEQ ID NO:37、SEQ ID NO:38、SEQ ID NO:39、SEQ ID NO:40或SEQID NO:41所示的多肽序列或由其组成。
优选地，根据本发明的被替换的内源性活化环包含与SEQ ID NO:39具有至少70％(例如至少80％或90％)序列同一性的多肽序列或由其组成。内源性活化环可包含与SEQ IDNO:39具有至少95％序列同一性的多肽序列或由其组成。更优选地，内源性活化环包含如SEQ ID NO:39所示的多肽序列或由其组成。
本发明涵盖方法和梭菌神经毒素，其中内源性活化环已被外源切割位点替代，所述外源切割位点是弗林蛋白酶切割位点，或内源性活化环已被包含弗林蛋白酶切割位点的外源性活化环替代。通常，弗林蛋白酶切割位点包含氨基酸序列Arg-Xaa-Yaa-Arg(SEQ IDNO:1)或由其组成，其中Xaa和Yaa可以各自独立地选自任何氨基酸。
不旨在将Xaa或Yaa限定为仅一种类型的氨基酸。因此，在Xaa和Yaa处的一个或多个残基可以独立地选自标准氨基酸：天冬氨酸、谷氨酸、精氨酸、赖氨酸、组氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、甲硫氨酸、色氨酸、半胱氨酸、丙氨酸、甘氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸和苯丙氨酸。在Yaa位置的一个或多个残基可以独立地选自标准氨基酸：天冬氨酸、谷氨酸、精氨酸、赖氨酸、组氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、甲硫氨酸、色氨酸、半胱氨酸、丙氨酸、甘氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸和苯丙氨酸。
替代地/另外地，在Xaa或Yaa位置上存在的一个或多个残基可以独立地选自非标准氨基酸(不是上述标准组20的一部分的氨基酸)。举例来说，非标准氨基酸可包括4-羟基脯氨酸、6-N-甲基赖氨酸、2-氨基异丁酸、异缬氨酸、α-甲基丝氨酸、反式3-甲基脯氨酸、2,4-甲基脯氨酸、顺式-4-羟基脯氨酸、反式-4-羟基脯氨酸、N-甲基甘氨酸、别苏氨酸、甲基苏氨酸、羟乙基半胱氨酸、羟乙基高半胱氨酸、硝基谷氨酰胺、高谷氨酰胺、哌酸、叔亮氨酸、正缬氨酸、2-氮杂苯丙氨酸、3-氮杂苯丙氨酸、4-氮杂苯丙氨酸、L-鸟氨酸、L-2-氨基-3-胍基丙酸、或赖氨酸、精氨酸和/或鸟氨酸的D-异构体,以及4-氟苯丙氨酸。将非标准氨基酸引入蛋白质的方法是本领域已知的，包括使用大肠杆菌营养缺陷型表达宿主的重组蛋白质合成。
下表列出了标准氨基酸的特性：
| 氨基酸 | 侧链 | ||
| 天冬氨酸 | Asp | D | 带电(酸性) |
| 谷氨酸 | Glu | E | 带电(酸性) |
| 精氨酸 | Arg | R | 带电(碱性) |
| 赖氨酸 | Lys | K | 带电(碱性) |
| 组氨酸 | His | H | 不带电(极性) |
| 天冬酰胺 | Asn | N | 不带电(极性) |
| 谷氨酰胺 | Gln | Q | 不带电(极性) |
| 丝氨酸 | Ser | S | 不带电(极性) |
| 苏氨酸 | Thr | T | 不带电(极性) |
| 酪氨酸 | Tyr | Y | 不带电(极性) |
| 甲硫氨酸 | Met | M | 不带电(极性) |
| 色氨酸 | Trp | W | 不带电(极性) |
| 半胱氨酸 | Cys | C | 不带电(极性) |
| 丙氨酸 | Ala | A | 不带电(疏水) |
| 甘氨酸 | Gly | G | 不带电(疏水) |
| 缬氨酸 | Val | V | 不带电(疏水) |
| 亮氨酸 | Leu | L | 不带电(疏水) |
| 异亮氨酸 | Ile | I | 不带电(疏水) |
| 脯氨酸 | Pro | P | 不带电(疏水) |
| 苯丙氨酸 | Phe | F | 不带电(疏水) |
以下氨基酸被认为是带电荷的氨基酸：天冬氨酸(负)、谷氨酸(负)、精氨酸(正)和赖氨酸(正)。
通常，Xaa是小的和/或亲水性氨基酸和/或Yaa是带正电荷的氨基酸。本发明的弗林蛋白酶切割位点的优选实例包括包含Arg-Xaa-Lys-Arg(SEQ ID NO:2)、Arg-Xaa-Arg-Arg(SEQ ID NO:3)和Arg-Lys-Lys-Arg(SEQ ID NO:4)或由其组成的氨基酸序列。
本发明的弗林蛋白酶切割位点可包含核心或最小弗林蛋白酶切割位点(如SEQ IDNO:1、SEQ ID NO:2、SEQ ID NO:3或SEQ ID NO:4中的任一个)和一个或多个另外的氨基酸或由其组成。优选地，本发明的弗林蛋白酶切割位点可以包含核心或最小弗林蛋白酶切割位点(如SEQ ID NO:2、SEQ ID NO:3或SEQ ID NO:4中的任一个)和一个或多个另外的氨基酸或由其组成。所述一个或多个另外的氨基酸可以是核心弗林蛋白酶切割位点的N-末端和/或C-末端。所述一个或多个另外的氨基酸可以优选地选自小的和/或亲水性氨基酸(如丝氨酸和/或赖氨酸)。
在N端侧紧邻核心弗林蛋白酶切割位点(例如SEQ ID NO:1、SEQ ID NO:2、SEQ IDNO:3或SEQ ID NO:4)的N-末端Arg的一个或多个氨基酸残基(如两个、三个、四个、五个、六个、七个、八个、九个或十个氨基酸)可以是极性(亲水性)氨基酸(例如丝氨酸或苏氨酸)或带正电荷的氨基酸(例如赖氨酸或精氨酸)。
替代地或另外地，在C端侧紧邻核心弗林蛋白酶切割位点(例如SEQ ID NO:1、SEQID NO:2、SEQ ID NO:3或SEQ ID NO:4)的C-末端Arg的一个或多个氨基酸残基(如两个、三个、四个、五个、六个、七个、八个、九个或十个氨基酸)可以是极性(亲水性)氨基酸(例如丝氨酸或苏氨酸)或带正电荷的氨基酸(例如赖氨酸或精氨酸)。
优选地，在N端侧紧邻核心弗林蛋白酶切割位点(例如SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3或SEQ ID NO:4)的N-末端Arg的一个或多个氨基酸残基(如两个、三个、四个、五个、六个、七个、八个、九个或十个氨基酸)是极性(亲水性)氨基酸(例如丝氨酸或苏氨酸)或带正电荷的氨基酸(例如赖氨酸或精氨酸)，并且在C端侧紧邻核心弗林蛋白酶切割位点(例如SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3或SEQ ID NO:4)的C-末端Arg的一个或多个氨基酸残基(如两个、三个、四个、五个、六个、七个、八个、九个或十个氨基酸)可以是极性(亲水性)氨基酸(例如丝氨酸或苏氨酸)或带正电荷的氨基酸(例如赖氨酸或精氨酸)。
包含一个或多个另外的氨基酸的弗林蛋白酶切割位点的非限制性实例包括：KQKSSNSRKKR(SEQ ID NO:5)、SRKKRS(SEQ ID NO:6)、SRKRRS(SEQ ID NO:7)、SKRKKRS(SEQID NO:8)、SKRKRRS(SEQ ID NO:9)、TSSKSRRRKKRSTS(SEQ ID NO:10)、AGLITGGRRTRRSI(SEQID NO:11)、KVADSLSTRKQKR(SEQ ID NO:12)和LATGLRNTSQRSRRRKKRGL(SEQ ID NO:13)。
在一些实施方案中，本发明的弗林蛋白酶切割位点与SEQ ID NO:5具有至少70％序列同一性。弗林蛋白酶切割位点可以与SEQ ID NO:5具有至少80％、85％或90％序列同一性。优选地，弗林蛋白酶切割位点与SEQ ID NO:5具有至少95％的序列同一性。更优选地，弗林蛋白酶切割位点与SEQ ID NO:5具有至少99％序列同一性。特别优选的是包含SEQ IDNO:5或由其组成的弗林蛋白酶切割位点。
本发明的工程化梭菌神经毒素可包含含有如本文所述的任何弗林蛋白酶切割位点的外源性活化环。如本文所述，可以通过替换梭菌神经毒素的内源性活化环的一个或多个氨基酸来产生外源性活化环。在一些优选的实施方案中，内源性活化环的置换的氨基酸被具有相同氨基酸数目的弗林蛋白酶切割位点或外源性活化环置换。换句话说，举例来说，如果在内源性活化环中替换五个氨基酸，则替换的弗林蛋白酶切割位点或包含所述弗林蛋白酶切割位点的外源性活化环具有五个氨基酸。如果在内源性活化环中10个氨基酸被替换，则替换的弗林蛋白酶切割位点或包含所述弗林蛋白酶切割位点的外源性活化环具有10个氨基酸。
此类外源性活化环的非限制性实例包括CVRGIITSKTKSLSRKKRSALNDLC(SEQ IDNO:14)、CVRGIITSKTKSLSRKRRSALNDLC(SEQ ID NO:15)、CVRGIITSKTKSSKRKKRSALNDLC(SEQID NO:16)、CVRGIITSKTKSSKRKRRSALNDLC(SEQ ID NO:17)、CVRGITSSKSRRRKKRSTSALNDLC(SEQ ID NO:18)、CVRGIAGLITGGRRTRRSIALNDLC(SEQ ID NO:19)、CVRGIIKVADSLSTRKQKRALNDLC(SEQ ID NO:20)、CVRGILATGLRNTSQRSRRRKKRGLALNDLC(SEQID NO:21)和CVRGIKQKSSNSRKKRSTSALNDLC(SEQ ID NO:22)，其全部衍生自BoNT/A1活化环。SEQ ID NO:22是外源性活化环的优选实例。
本发明提供了一种用于制备根据本发明的工程化梭菌神经毒素的方法，其包括通过用外源性活化环或外源性切割位点替换梭菌神经毒素的内源性活化环(或其部分)，由此提供工程化的梭菌神经毒素，其中外源性切割位点是如本文所述的弗林蛋白酶切割位点，或外源性活化环包含所述弗林蛋白酶切割位点。通常，所述弗林蛋白酶切割位点包含SEQID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4或SEQ ID NO:5的氨基酸序列或由其组成，或所述外源性活化环包含所述弗林蛋白酶切割位点。
本发明提供了工程化梭菌神经毒素(例如可通过本发明的方法获得)，其中梭菌神经毒素的内源性活化环(或其部分)已被外源性活化环或外源切割位点替换，从而提供工程化的梭菌神经毒素，其中外源性切割位点是如本文所述的弗林蛋白酶切割位点，或外源性活化环包含所述弗林蛋白酶切割位点。通常，所述弗林蛋白酶切割位点包含SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4或SEQ ID NO:5的氨基酸序列或由其组成，或所述外源性活化环包含所述弗林蛋白酶切割位点。
本发明的梭菌神经毒素(例如工程化梭菌神经毒素)可由与SEQ ID NO:23具有至少70％序列同一性的核苷酸序列编码。本发明的梭菌神经毒素可以由与SEQ ID NO:23具有至少80％或90％序列同一性的核苷酸序列编码。优选地，本发明的梭菌神经毒素可以由包含SEQ ID NO:23(更优选由其组成)的核苷酸序列编码。
本发明的梭菌神经毒素(例如工程化梭菌神经毒素)可包含与SEQ ID NO:24或70至78中的一项或多项具有至少70％序列同一性的多肽序列。本发明的梭菌神经毒素可以包含与SEQ ID NO:24或70至78中的一项或多项具有至少80％或90％序列同一性的多肽序列。优选地，本发明的梭菌神经毒素可以包含SEQ ID NO:24或70至78中任一个所示的多肽序列(更优选地由其组成)。
本发明的梭菌神经毒素(例如工程化梭菌神经毒素)优选是BoNT/A，甚至更优选BoNT/A1，其中梭菌神经毒素由与SEQ ID NO:23具有至少70％序列同一性的核苷酸序列编码。梭菌神经毒素可以由与SEQ ID NO:23具有至少80％或90％序列同一性的核苷酸序列编码。优选地，梭菌神经毒素由包含SEQ ID NO:23(或由其组成)的核苷酸序列编码。本发明的梭菌神经毒素优选是BoNT/A，甚至更优选是BoNT/A1，其中梭菌神经毒素包含与SEQ ID NO:24具有至少70％序列同一性的多肽序列。梭菌神经毒素可以包含与SEQ ID NO:24具有至少80％或90％序列同一性的多肽序列。优选地，梭菌神经毒素包含SEQ ID NO:24所示的多肽序列(或由其组成)。
本发明的多肽序列(或编码其的核苷酸序列)可以包括纯化标签，例如His标签。本发明还旨在包括其中纯化标签被去除的多肽序列(和编码其的核苷酸序列)。
梭菌神经毒素
梭菌神经毒素(例如工程化前)可以是BoNT/A。示例性参考BoNT/A序列如SEQ IDNO:25所示。
梭菌神经毒素(例如工程化前)可以是BoNT/B。示例性参考BoNT/B序列如SEQ IDNO:26所示。
梭菌神经毒素(例如工程化前)可以是BoNT/C。示例性参考BoNT/C1序列如SEQ IDNO:27所示。
梭菌神经毒素(例如工程化前)可以是BoNT/D。示例性参考BoNT/D序列如SEQ IDNO:28所示。
梭菌神经毒素(例如工程化前)可以是BoNT/E。示例性参考BoNT/E序列如SEQ IDNO:29所示。
梭菌神经毒素(例如工程化前)可以是BoNT/F。示例性参考BoNT/F序列如SEQ IDNO:30所示。
梭菌神经毒素(例如工程化前)可以是BoNT/G。示例性参考BoNT/G序列如SEQ IDNO:31所示。
梭菌神经毒素(例如工程化前)可以是BoNT/X。示例性参考BoNT/X序列如SEQ IDNO:32所示。
梭菌神经毒素(例如工程化前)可以是TeNT。示例性参考TeNT序列显示如SEQ IDNO:33所示。
如上所述，活化的梭菌神经毒素由两条多肽链形成，即分子量为约100kDa的重链(H链)和分子量为约50kDa的轻链(L链)。H链包含C-末端靶向组分(受体结合结构域或HC结构域)和N-末端易位组分(HN结构域)。
轻链参考序列的实例包括：
A型肉毒神经毒素：氨基酸残基1-448
B型肉毒神经毒素：氨基酸残基1-440
C1型肉毒神经毒素：氨基酸残基1-441
D型肉毒神经毒素：氨基酸残基1-445
E型肉毒神经毒素：氨基酸残基1-422
F型肉毒神经毒素：氨基酸残基1-439
G型肉毒神经毒素：氨基酸残基1-441
破伤风神经毒素：氨基酸残基1-457
对于最近鉴定的BoNT/X，据报道L链对应于其氨基酸1-439，其中L链边界可能变化约25个氨基酸(例如1-414或1-464)。
以上鉴定的参考序列应当被认为是指导，因为根据亚血清型可能发生轻微变化。举例来说，US2007/0166332(通过引用整体并入本文)引用了略微不同的梭菌序列：
A型肉毒神经毒素：氨基酸残基M1-K448
B型肉毒神经毒素：氨基酸残基M1-K441
C1型肉毒神经毒素：氨基酸残基M1-K449
D型肉毒神经毒素：氨基酸残基M1-R445
E型肉毒神经毒素：氨基酸残基M1-R422
F型肉毒神经毒素：氨基酸残基M1-K439
G型肉毒神经毒素：氨基酸残基M1-K446
破伤风神经毒素：氨基酸残基M1-A457
或者，梭菌神经毒素L链可以定义为第一个氨基酸(包括或不包括起始甲硫氨酸残基)至内源性活化环的第一个半胱氨酸残基。另外地或替代地，梭菌神经毒素L链可以定义为位于内源性活化环内切割位点的N-末端的氨基酸序列。
梭菌神经毒素L链可以定义为包含金属配位HExxH基序(SEQ ID NO:58)的梭菌神经毒素结构域，其通常用于切割SNARE蛋白底物。
术语“轻链”(或“L-链”)涵盖其变体和片段，条件是所述变体和片段仍然表现出非细胞毒性蛋白酶活性(其可以使用本领域已知的标准测定来确定，其实例在本文中描述)。举例来说，变体可以与参考L链具有至少70％，优选至少80％，更优选至少90％，最优选至少95％或至少98％的氨基酸序列同源性。与L链相关使用时，术语片段意指具有参考L链的至少200个，优选至少250个，更优选至少300个，甚至更优选至少350个和最优选至少400个氨基酸残基的肽。在梭菌L链的情况下，片段优选参考L链的至少300个，更优选至少350个，最优选至少400个氨基酸残基。本发明的L链“片段”包括基于参考序列的变体L链的片段。
梭菌神经毒素H链可以定义为内源性活化环的第二个半胱氨酸直至最后一个氨基酸。另外地或替代地，梭菌神经毒素H链可以定义为从氨基酸序列C-末端的开始至内源性活化环内的切割位点。另外地或替代地，梭菌神经毒素H-链可以定义为从氨基酸C-末端开始到在L-和H-链之间形成二硫键并因此定义内源性活化环的C-末端的半胱氨酸残基(通常是第二个半胱氨酸残基)。
易位结构域是能够使蛋白酶易位到靶细胞中的分子，从而在靶细胞的细胞质内发生蛋白酶活性的功能性表达。可以通过许多常规测定法中的任何一种来确认任何分子(例如蛋白质或肽)是否具有本发明必需的易位功能。
例如，Shone C.(1987)描述了使用脂质体的体外测定法，所述脂质体受到测试分子的攻击。通过从脂质体中释放的K+和/或标记的NAD来确认必需的易位功能的存在，所述K+和/或标记的NAD可以容易地监测[参见Shone C.(1987)Eur.J.Biochem；第167卷(1):第175-180页]。
Blaustein R.(1987)提供了另一个示例，其描述了使用平面磷脂双层膜的简单的体外测定法。用测试分子攻击膜，并通过所述膜的跨膜电导的增加来确认必需的易位功能[参见Blaustein(1987)FEBS Letts；第226卷,第1号:第115-120页]。
Methods in Enzymology Vol 220and 221,Membrane Fusion Techniques,PartsA and B,Academic Press 1993提供了能够评估膜融合并因此鉴定适用于本发明的易位结构域的其他方法。
本发明还包括易位结构域变体和/或片段，只要所述结构域变体仍显示出必需的易位活性。举例来说，变体可与参考易位结构域具有至少70％，优选至少80％，更优选至少90％，最优选至少95％或至少98％的氨基酸序列同源性。当相对于易位结构域使用时，术语片段是指肽，其具有参考易位结构域的至少20个，优选至少40个，更优选至少80个，最优选至少100个氨基酸残基。在梭菌易位结构域的情况下，该片段优选具有参考易位结构域(例如HN结构域)的至少100个，优选至少150个，更优选至少200个，最优选至少250个氨基酸残基。本发明的易位“片段”包括基于参考序列的易位结构域变体的片段。
易位结构域优选地能够在低pH条件下在脂质膜中形成离子可渗透的孔。优选地，已经发现仅使用能够在内体膜内形成孔的蛋白质分子的那些部分。
易位结构域可获自微生物蛋白来源，特别是获自细菌或病毒蛋白来源。因此，易位结构域可以是酶的易位结构域，例如，细菌毒素或病毒蛋白的易位结构域。
众所周知，细菌毒素分子的某些结构域能够形成此类孔。还已知病毒表达的膜融合蛋白的某些易位结构域能够形成此类孔。这样的结构域可以在本发明中使用。
易位结构域可以是梭菌来源的，例如HN结构域(或其功能性组分)。HN表示梭菌神经毒素的H链的一部分或片段(大约等同于H链的氨基末端的一半)，或与完整H链中的该片段相对应的结构域。可通过删除HC氨基酸序列去除H链的HC功能(通过核酸酶或蛋白酶处理，在DNA合成水平上或在合成后水平上去除)。可替代地，可以通过化学或生物处理使HC功能失活。因此，H链可能不能结合天然梭菌神经毒素(即全毒素)结合的靶细胞上的结合位点。
合适的(参考)易位结构域的实例包括：
A型肉毒神经毒素-氨基酸残基(449-871)
B型肉毒神经毒素-氨基酸残基(441-858)
C型肉毒神经毒素-氨基酸残基(442-866)
D型肉毒神经毒素-氨基酸残基(446-862)
E型肉毒神经毒素-氨基酸残基(423-845)
F型肉毒神经毒素-氨基酸残基(440-864)
G型肉毒神经毒素-氨基酸残基(442-863)
X型肉毒神经毒素-氨基酸残基(461-890)
破伤风神经毒素-氨基酸残基(458-879)
对于最近鉴定的BoNT/X，据报道易位结构域对应于其氨基酸460-890，其中L链和HC边界可能变化约10个氨基酸(例如461-889或454-891)。
以上鉴定的参考序列应被视为指导，因为根据血清亚型可能会发生细微变化。举例来说，US2007/0166332(通过引用整体并入本文)引用了略有不同的梭菌序列：
A型肉毒神经毒素-氨基酸残基(A449-K871)
B型肉毒神经毒素-氨基酸残基(A442-S858)
C型肉毒神经毒素-氨基酸残基(T450-N866)
D型肉毒神经毒素-氨基酸残基(D446-N862)
E型肉毒神经毒素-氨基酸残基(K423-K845)
F型肉毒神经毒素-氨基酸残基(A440-K864)
G型肉毒神经毒素-氨基酸残基(S447-S863)
破伤风神经毒素-氨基酸残基(S458-V879)
在本发明的上下文中，多种具有易位结构域的梭菌神经毒素HN区可用于本发明的方面，只要这些活性片段可以促进非细胞毒性蛋白酶(例如梭菌L-链)从细胞内的小泡释放进入靶细胞的细胞质，从而参与执行整个细胞机制，由此梭菌神经毒素通过蛋白水解裂解底物。梭菌神经毒素重链的HN区长度约为410-430个氨基酸，并包含一个易位结构域。研究表明，来自梭菌神经毒素重链的HN区的全长对于易位结构域的易位活性不是必需的。因此，在本发明的上下文中，易位结构域可以包括包含易位结构域的梭菌神经毒素HN区，其具有例如至少350个氨基酸，至少375个氨基酸，至少400个氨基酸和至少425个氨基酸的长度。还被涵盖的是，包含易位结构域的梭菌神经毒素HN区，其具有例如至多350个氨基酸，至多375个氨基酸，至多400个氨基酸和至多425个氨基酸的长度。
有关肉毒杆菌(Clostridium botulinum)和破伤风梭菌产生毒素的遗传基础的更多详细信息，参见Henderson等人(1997)in The Clostridia:Molecular Biology andPathogenesis,Academic press。
术语HN包括天然存在的神经毒素HN部分和修饰的HN部分，所述修饰的HN部分具有在自然界中不存在氨基酸序列和/或合成的氨基酸残基，只要该修饰的HN部分仍表现出上述易位功能。
备选地，易位结构域可以是非梭菌来源的。非梭菌(参考)易位结构域来源的示例包括但不限于白喉毒素的易位结构域[O’Keefe等人,Proc.Natl.Acad.Sci.USA(1992)89,6202-6206；Silverman等人,J.Biol.Chem.(1993)269,22524-22532；和London,E.(1992)Biochem.Biophys.Acta.,1112,pp.25-51],A型假单胞菌外毒素的易位结构域[Prior等人Biochemistry(1992)31,3555-3559]，炭疽毒素的易位结构域[Blanke等人Proc.Natl.Acad.Sci.USA(1996)93,8437-8442]，各种具有易位功能的融合或疏水性肽[Plank等人J.Biol.Chem.(1994)269,12918-12924；和Wagner等人(1992)PNAS,89,pp.7934-7938]，和两亲性肽[Murata等人(1992)Biochem.,31，第1986-1992页]。易位结构域可以反映天然存在的蛋白质中存在的易位结构域，或者可以包含氨基酸变异，只要变异不破坏易位结构域的易位能力。
适用于本发明的病毒(参考)易位结构域的具体示例包括病毒表达的膜融合蛋白的某些易位结构域。例如，Wagner等人(1992)和Murata等人(1992)描述了源自流感病毒血凝素N-末端区域的许多融合和两亲性肽的易位(即,膜融合和囊泡化)功能。其他已知具有所需易位活性的病毒表达的膜融合蛋白是Semliki森林病毒(SFV)融合肽的易位结构域、水疱性口炎病毒(VSV)糖蛋白G的易位结构域、SER病毒F蛋白的易位结构域和泡沫病毒包膜糖蛋白的易位结构域。病毒编码的Aspike蛋白在本发明的上下文中具有特定的应用，例如，SFV的E1蛋白和VSV的G蛋白的G蛋白。
表(下表)中列出的(参考)易位结构域的使用包括其序列变体的使用。变体可以包含一个或多个保守核酸取代和/或核酸删除或插入，只要该变体具有必需的易位功能。变体还可以包含一个或多个氨基酸取代和/或氨基酸删除或插入，只要该变体具有必需的易位功能。
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梭菌神经毒素HC结构域参考序列的实例包括：
BoNT/A-N872-L1296
BoNT/B-E859-E1291
BoNT/C1-N867-E1291
BoNT/D-S863-E1276
BoNT/E-R846-K1252
BoNT/F-K865-E1274
BoNT/G-N864-E1297
TeNT-I880-D1315
对于最近鉴定的BoNT/X，据报道HC结构域对应于其氨基酸893-1306，其中结构域边界可能相差约25个氨基酸(例如，868-1306或918-1306)。
本文所述的梭菌神经毒素可进一步包含易位促进结构域。所述结构域促进将非细胞毒性蛋白酶递送至靶细胞的细胞质中，并且描述在例如，WO 08/008803和WO 08/008805中，其各自通过引用并入本文。
举例来说，合适的易位促进结构域包括包膜病毒融合(fusogenic)肽结构域，例如，合适的融合肽结构域包括流感病毒融合肽结构域(例如23个氨基酸的甲型流感病毒融合肽结构域)、α病毒融合肽结构域(例如26个氨基酸的Semliki森林病毒融合肽结构域)、水疱病毒融合肽结构域(例如21个氨基酸的水疱性口炎病毒融合肽结构域)、呼吸道病毒融合肽结构域(例如25个氨基酸的仙台病毒融合肽结构域)、麻疹病毒融合肽结构域(例如25个氨基酸的犬瘟热病毒融合肽结构域)、avulavirus病毒融合肽结构域(例如25个氨基酸的新城病毒融合肽结构域)、henipavirus病毒融合肽结构域(例如25个氨基酸的亨德拉病毒融合肽结构域)、间质性肺炎病毒(metapneumovirus)融合肽结构域(例如25个氨基酸的人间质性肺炎病毒融合肽结构域)或spumavirus病毒融合肽结构域，如猿猴泡沫病毒融合肽结构域；或其片段或变体。
作为进一步的示例，易位促进结构域可包含梭菌神经毒素HCN结构域或其片段或变体。更详细地，梭菌神经毒素HCN易位促进结构域可以具有至少200个氨基酸，至少225个氨基酸，至少250个氨基酸，至少275个氨基酸的长度。在这方面，梭菌神经毒素HCN易位促进结构域优选具有至多200个氨基酸，至多225个氨基酸，至多250个氨基酸或至多275个氨基酸的长度。具体(参考)示例包括：
A型肉毒神经毒素-氨基酸残基(872-1110)
B型肉毒神经毒素-氨基酸残基(859-1097)
C型肉毒神经毒素-氨基酸残基(867-1111)
D型肉毒神经毒素-氨基酸残基(863-1098)
E型肉毒神经毒素-氨基酸残基(846-1085)
F型肉毒神经毒素-氨基酸残基(865-1105)
G型肉毒神经毒素-氨基酸残基(864-1105)
X型肉毒神经毒素-氨基酸残基(890-1121)
破伤风神经毒素-氨基酸残基(880-1127)
上述序列位置可能会根据血清型/亚型略有差别，合适的(参考)梭菌神经毒素HCN结构域的其他示例包括：
A型肉毒神经毒素-氨基酸残基(874-1110)
B型肉毒神经毒素-氨基酸残基(861-1097)
C型肉毒神经毒素-氨基酸残基(869-1111)
D型肉毒神经毒素-氨基酸残基(865-1098)
E型肉毒神经毒素-氨基酸残基(848-1085)
F型肉毒神经毒素-氨基酸残基(867-1105)
G型肉毒神经毒素-氨基酸残基(866-1105)
破伤风神经毒素-氨基酸残基(882-1127)
任何上述促进结构域可与任何适用于本发明的前述易位结构域肽组合。因此，举例来说，非梭菌促进结构域可以与非梭菌易位结构域肽或与梭菌易位结构域肽组合。或者，可将梭菌神经毒素HCN易位促进结构域与非梭菌易位结构域肽组合。或者，可将梭菌神经毒素HCN促进结构域与梭菌易位结构域肽组合，其示例包括：
A型肉毒神经毒素-氨基酸残基(449-1110)
B型肉毒神经毒素-氨基酸残基(442-1097)
C型肉毒神经毒素-氨基酸残基(450-1111)
D型肉毒神经毒素-氨基酸残基(446-1098)
E型肉毒神经毒素-氨基酸残基(423-1085)
F型肉毒神经毒素-氨基酸残基(440-1105)
G型肉毒神经毒素-氨基酸残基(447-1105)
破伤风神经毒素-氨基酸残基(458-1127)
在一些实施方案中，本发明的梭菌神经毒素可缺少梭菌神经毒素的功能性HC结构域。因此，在结合测定法中，所述梭菌神经毒素不能结合大鼠突触体膜(通过梭菌神HC组分)，如在Shone等人(1985)Eur.J.Biochem.151,75-82所述。梭菌神经毒素可以优选缺少梭菌神经毒素全毒素的最后50个C-末端氨基酸。梭菌神经毒素可以优选缺少梭菌神经毒素全毒素的最后100个，优选最后150个，更优选最后200个，特别优选最后250个，最优选最后300个C-末端氨基酸残基。或者，可以通过诱变消除/降低HC的结合活性-举例来说，简单参照BoNT/A，神经节苷脂结合口袋中的一个或两个氨基酸残基突变(W1266到L和Y1267到F)的修饰导致HC区失去其受体结合功能。可以对非A型血清型的梭菌肽组分进行类似的突变，例如，基于肉毒杆菌B具有突变(W1262至L和Y1263至F)或肉毒杆菌E(W1224至L和Y1225至F)的构建体。活性位点的其他突变实现了相同的HC受体结合活性的消除，例如肉毒杆菌A型毒素中的Y1267S和其他梭菌神经毒素中相应的高度保守的残基。Rummel等(2004)(MolecularMicrobiol.51:631-634)中描述了该突变以及其他突变的细节，其通过引用并入本文。
天然梭菌神经毒素的HC肽包含约400-440个氨基酸残基，并由两个功能不同的结构域组成，每个结构域约25kDa，即，N-末端区域(通常称为HCN肽或结构域)和C-末端区域(通常称为HCC肽或结构域)。以下出版物已证实了这一事实，在此通过引用将其整体并入本文：Umland TC(1997)Nat.Struct.Biol.4:788-792；Herreros J(2000)Biochem.J.347:199-204；Halpern J(1993)J.Biol.Chem.268:15,pp.11188-11192；Rummel A(2007)PNAS104:359-364；Lacey DB(1998)Nat.Struct.Biol.5:898-902；Knapp(1998)Am.Cryst.Assoc.Abstract Papers 25:90；Swaminathan and Eswaramoorthy(2000)Nat.Struct.Biol.7:1751-1759；and Rummel A(2004)Mol.Microbiol.51(3),631-643。此外，已经有充分的文献证明，构成C-末端160-200个氨基酸残基的C-末端区域(HCC)负责梭菌神经毒素与其天然细胞受体(即神经肌接头处的神经末梢)的结合，-上述出版物也证实了这一事实。因此，贯穿本说明书，提及缺少功能性重链HC肽(或结构域)、使得重链不能与天然梭菌神经毒素结合的细胞表面受体结合的梭菌重链，意味着该梭菌重链仅缺少功能性HCC肽。换句话说，HCC肽区域可以被部分或全部删除，或以其他方式修饰(例如，通过常规化学或蛋白水解处理)以失活其对神经肌接头处神经末端的天然结合能力。
因此，本发明的梭菌神经毒素HN肽可以是C-末端延伸的，即，其可以与全部或部分梭菌神经毒素HC结构域(例如，HCN、HCC或HC结构域)缔合。本文提及本发明的梭菌神经毒素HN肽包括这样的C-末端延伸的HN肽，其包含一个或多个来自梭菌神经毒素HC结构域的氨基酸残基。或者，本发明的梭菌神经毒素HN肽不与全部或部分梭菌神经毒素HC结构域(例如，HCN、HCC或HC结构域)缔合(或缺乏全部或部分梭菌神经毒素HC结构域(例如，HCN、HCC或HC结构域))。
通常，如果本发明的梭菌神经毒素或本发明的梭菌神经毒素HN肽缺失全部或部分的梭菌神经毒素的C-末端肽部分(HCC)，其因此缺失天然梭菌神经毒素的HC结合功能。举例来说，C-末端延伸的梭菌HN肽可以缺少梭菌神经毒素重链的C-末端的40个氨基酸残基，或C-末端的60个氨基酸残基，或C-末端的80个氨基酸残基，或C-末端的100个氨基酸残基，或C-末端的120个氨基酸残基，或C-末端的140个氨基酸残基，或C-末端的150个氨基酸残基，或C-末端的160个氨基酸残基。或者，本发明的梭菌HN肽可以缺少梭菌神经毒素的完整C-末端肽部分(HCC)，因此缺少天然梭菌神经毒素的HC结合功能。举例来说，梭菌HN肽可以缺少梭菌神经毒素重链的C-末端的165个氨基酸残基，或C-末端的170个氨基酸残基，或C-末端的175个氨基酸残基，或C-末端的180个氨基酸残基，或C-末端的185个氨基酸残基，或C-末端的190个氨基酸残基，或C-末端的195个氨基酸残基。进一步举例来说，本发明的梭菌HN肽缺少选自以下的梭菌HCC参考序列：
A型肉毒神经毒素-氨基酸残基(Y1111-L1296)
B型肉毒神经毒素-氨基酸残基(Y1098-E1291)
C型肉毒神经毒素-氨基酸残基(Y1112-E1291)
D型肉毒神经毒素-氨基酸残基(Y1099-E1276)
E型肉毒神经毒素-氨基酸残基(Y1086-K1252)
F型肉毒神经毒素-氨基酸残基(Y1106-E1274)
G型肉毒神经毒素-氨基酸残基(Y1106-E1297)
X型肉毒神经毒素-氨基酸残基(Y1122-E1306)
破伤风神经毒素-氨基酸残基(Y1128-D1315)。
以上鉴定的参考序列应被视为指导，因为根据血清亚型可能会发生细微变化。
本发明适用于多种不同的梭菌神经毒素。因此，在本发明的上下文中，术语“梭菌神经毒素”包括由以下梭菌产生的毒素：肉毒杆菌(肉毒神经毒素血清型A、B、C1、D、E、F、G、H和X)，破伤风梭菌(破伤风神经毒素)，丁酸梭菌(肉毒神经毒素血清型E)和巴拉特梭菌(肉毒神经毒素血清型F)，以及修饰的梭菌神经毒素或衍生自上述物质的衍生物。术语“梭菌神经毒素”还包括血清型H的肉毒神经毒素。优选，梭菌神经毒素是BoNT/A，更优选BoNT/A1。
肉毒神经毒素(BoNT)是由肉毒杆菌产生的一种大蛋白复合物形式，由BoNT本身与许多辅助蛋白复合组成。目前有九种不同类别的肉毒神经毒素，即：肉毒神经毒素血清型A、B、C1、D、E、F、G、H和X，其均具有相似的结构和作用方式。可以基于通过特异性中和抗血清的失活来区分不同的BoNT血清型，其中通过血清型的这种分类与氨基酸水平的序列同一性百分比相关。根据氨基酸序列同一性百分比，将给定血清型的BoNT蛋白进一步分为不同的亚型。
BoNT在胃肠道中吸收，进入大循环后，与胆碱能神经末梢的突触前膜结合并阻止其神经递质乙酰胆碱的释放。BoNT/B、BoNT/D、BoNT/F和BoNT/G裂解小突触泡蛋白/囊泡相关膜蛋白(VAMP)；BoNT/C1、BoNT/A和BoNT/E裂解25kDa的突触体相关蛋白(SNAP-25)；BoNT/C1裂解突触融合蛋白。发现BoNT/X可以裂解SNAP-25、VAMP1、VAMP2、VAMP3、VAMP4、VAMP5、Ykt6和突触融合蛋白1。
破伤风梭菌产生单一血清型的破伤风毒素。丁酸梭菌产生BoNT/E，而巴拉特梭菌产生BoNT/F。
术语“梭菌神经毒素”也意图包括修饰的梭菌神经毒素及其衍生物，包括但不限于以下所述的那些。修饰的梭菌神经毒素或衍生物可包含一个或多个氨基酸，所述氨基酸与梭菌神经毒素的天然(未修饰)形式相比已被修饰，或者所述修饰的梭菌神经毒素或衍生物可包含一个或多个插入的在天然(未修饰)形式中不存在的氨基酸。举例来说，相对于天然(未修饰的)梭菌神经毒素序列，修饰的梭菌神经毒素可以在一个或多个结构域中具有修饰的氨基酸序列。这样的修饰可以修饰毒素的功能方面，例如生物活性或持久性。因此，本发明的梭菌神经毒素可以是修饰的梭菌神经毒素，或修饰的梭菌神经毒素衍生物，或梭菌神经毒素衍生物。尤其是，本发明的工程化的梭菌神经毒素是工程化的修饰的梭菌神经毒素，或工程化的修饰的梭菌神经毒素衍生物，或工程化的梭菌神经毒素衍生物。
修饰的梭菌神经毒素可以在重链的氨基酸序列中具有一个或多个修饰(如修饰的HC结构域)，其中，所述修饰的重链以比天然(未修饰的)梭菌神经毒素更高或更低的亲合力与靶神经细胞结合。在HC结构域中这样的修饰可包括在HC结构域的神经节苷脂结合位点中的修饰残基，或在改变与神经节苷脂受体和/或靶神经细胞的蛋白受体的结合的蛋白(SV2或突触结合蛋白)结合位点中的修饰残基。此类修饰的梭菌神经毒素的示例描述于WO2006/027207和WO 2006/114308中，二者均在此通过引用整体并入本文。
修饰的梭菌神经毒素可在轻链的氨基酸序列中具有一个或多个修饰，例如在底物结合或催化结构域中的修饰，其可改变或修改修饰的L链的SNARE蛋白特异性。此类修饰的梭菌神经毒素的示例描述于WO 2010/120766和US 2011/0318385中，二者均在此通过引用整体并入本文。
修饰的梭菌神经毒素可包含一个或多个修饰，其增加或降低修饰的梭菌神经毒素的生物活性和/或生物持久性。例如，修饰的梭菌神经毒素可包含基于亮氨酸或酪氨酸的基序，其中所述基序增加或降低修饰的梭菌神经毒素的生物活性和/或生物持久性。合适的基于亮氨酸的基序包括xDxxxLL(SEQ ID NO:60)、xExxxLL(SEQ ID NO:61)、xExxxIL(SEQ IDNO:62)和xExxxLM(SEQ ID NO:63)(其中x是任何氨基酸)。合适的基于酪氨酸的基序包括Y-x-x-Hy(SEQ ID NO:64)(其中Hy是疏水性氨基酸)。包含基于亮氨酸和酪氨酸的基序的修饰的梭菌神经毒素的示例在WO 2002/008268中描述，其通过引用整体并入本文。
术语“梭菌神经毒素”旨在包括杂合和嵌合的梭菌神经毒素。杂合梭菌神经毒素包含来自一种梭菌神经毒素或其亚型的轻链的至少一部分，以及来自另一种梭菌神经毒素或梭菌神经毒素亚型的重链的至少一部分。在一个实施方案中，杂合梭菌神经毒素可包含来自一种梭菌神经毒素亚型的整个轻链和来自另一种梭菌神经毒素亚型的重链。在另一个实施方案中，嵌合的梭菌神经毒素可以包含一种梭菌神经毒素亚型的重链的一部分(例如结合结构域)，其中重链的另一部分来自另一种梭菌神经毒素亚型。嵌合梭菌神经毒素，尤其是嵌合BoNT，可以根据神经毒素的四个主要结构域的血清型或亚血清型来定义：L-链、HN、HCN和HCC(如本文定义的)。例如，SEQ ID NO:69的(工程化前的)LHN/A1-HCB1嵌合体可以描述为AABB嵌合体。类似地或可替代地，治疗元件可包含来自不同梭菌神经毒素的轻链部分。此类杂合或嵌合的梭菌神经毒素可用作，例如，向对给定梭菌神经毒素亚型具有免疫抗性的患者、向对给定梭菌神经毒素重链结合结构域可能具有低于平均受体浓度的患者、或向可能具有膜或囊泡毒素底物(例如SNAP-25，VAMP和突触融合蛋白)的蛋白酶抗性变体的患者递送此类梭菌神经毒素的治疗益处的手段。杂合和嵌合的梭菌神经毒素描述于US 8,071,110，其公开内容在此整体引用作为参考。因此，本发明的梭菌神经毒素是杂合梭菌神经毒素或嵌合梭菌神经毒素。尤其是，本发明的工程化的梭菌神经毒素是工程化的杂合梭菌神经毒素或工程化的嵌合梭菌神经毒素。
在一些优选的实施方案中，梭菌神经毒素是BoNT/A，其包含来自非BoNT/A梭菌神经毒素(例如，BoNT/A杂合体或嵌合体)的至少一个结构域。例如，本发明的梭菌神经毒素(包含弗林蛋白酶切割位点)可以包含：
i.BoNT/A L链和非BoNT/A HN和HC结构域；
ii.BoNT/A HN结构域和非BoNT/A L链和HC结构域；
iii.BoNT/A HC结构域和非BoNT/A L链和HN结构域；
iv.BoNT/A L链和HN结构域和非BoNT/A HC结构域；
v.BoNT/A L链和HC结构域和非BoNT/A HN结构域；或
vi.BoNT/A HN结构域和HC结构域和非BoNT/A L链。
作为非限制性实例，本发明的梭菌神经毒素(例如工程化的梭菌神经毒素)包含BoNT/A L-链和HN结构域和BoNT/B HC结构域(例如LHN/A1-HC/B1)。可以修饰以包含根据本发明的弗林蛋白酶切割位点的示例性非工程化LHN/A1-HCB1嵌合体在SEQ ID NO:69中给出。SEQ ID NO:69的LHN/A1-HCB1嵌合体的示例性工程化形式在SEQ ID NO:70中给出。本发明的梭菌神经毒素(例如工程化的梭菌神经毒素)可包含BoNT/A L-链和和HN结构域和BoNT/C1HC结构域。本发明的梭菌神经毒素(例如工程化的梭菌神经毒素)可包含BoNT/A L-链和和HN结构域和BoNT/D HC结构域。本发明的梭菌神经毒素(例如工程化的梭菌神经毒素)可包含BoNT/A L-链和和HN结构域和BoNT/E HC结构域。本发明的梭菌神经毒素(例如工程化的梭菌神经毒素)可包含BoNT/A L-链和和HN结构域和BoNT/F HC结构域。本发明的梭菌神经毒素(例如工程化的梭菌神经毒素)可包含BoNT/A L-链和和HN结构域和BoNT/G HC结构域。本发明的梭菌神经毒素(例如工程化的梭菌神经毒素)可包含BoNT/A L-链和和HN结构域和BoNT/X HC结构域。本发明的梭菌神经毒素(例如工程化的梭菌神经毒素)可包含BoNT/A L链和HN结构域和TeNT HC结构域。
例如，本发明的梭菌神经毒素(例如包含弗林蛋白酶切割位点的工程化梭菌神经毒素)可以包含：
i.BoNT/B L链和非BoNT/B HN和HC结构域；
ii.BoNT/B HN结构域和非BoNT/B L链和HC结构域；
iii.BoNT/B HC结构域和非BoNT/B L链和HN结构域；
iv.BoNT/B L链和HN结构域和非BoNT/B HC结构域；
v.BoNT/B L链和HC结构域和非BoNT/B HN结构域；或
vi.BoNT/B HN结构域和HC结构域和非BoNT/B L链。
例如，本发明的梭菌神经毒素(例如包含弗林蛋白酶切割位点的工程化梭菌神经毒素)可包含：
i.BoNT/C1 L链和非BoNT/C1 HN和HC结构域；
ii.BoNT/C1 HN结构域和非BoNT/C1 L链和HC结构域；
iii.BoNT/C1 HC结构域和非BoNT/C1 L链和HN结构域；
iv.BoNT/C1 L链和HN结构域和非BoNT/C1 HC结构域；
v.BoNT/C1 L链和HC结构域和非BoNT/C1 HN结构域；或
vi.BoNT/C1 HN结构域和HC结构域和非BoNT/C1 L链。
非限制性实例包括BoNT/C1嵌合体，其中非BoNT/C1元件来自BoNT/D(即BoNT/CD嵌合体)。
例如，本发明的梭菌神经毒素(例如包含弗林蛋白酶切割位点的工程化梭菌神经毒素)可包含：
i.BoNT/D L链和非BoNT/D HN和HC结构域；
ii.BoNT/D HN结构域和非BoNT/D L链和HC结构域；
iii.BoNT/D HC结构域和非BoNT/D L链和HN结构域；
iv.BoNT/D L链和HN结构域和非BoNT/D HC结构域；
v.BoNT/D L链和HC结构域和非BoNT/D HN结构域；或
vi.BoNT/D HN结构域和HC结构域和非BoNT/D L链。
非限制性实例包括BoNT/D嵌合体，其中非BoNT/D元件来自BoNT/C1(即BoNT/DC1嵌合体)。
例如，本发明的梭菌神经毒素(例如包含弗林蛋白酶切割位点的工程化梭菌神经毒素)可包含：
i.BoNT/E L链和非BoNT/E HN和HC结构域；
ii.BoNT/E HN结构域和非BoNT/E L链和HC结构域；
iii.BoNT/E HC结构域和非BoNT/E L链和HN结构域；
iv.BoNT/E L链和HN结构域和非BoNT/E HC结构域；
v.BoNT/E L链和HC结构域和非BoNT/E HN结构域；或
vi.BoNT/E HN结构域和HC结构域和非BoNT/E L链。
例如，本发明的梭菌神经毒素(例如包含弗林蛋白酶切割位点的工程化梭菌神经毒素)可包含：
i.BoNT/F L链和非BoNT/F HN和HC结构域；
ii.BoNT/F HN结构域和非BoNT/F L链和HC结构域；
iii.BoNT/F HC结构域和非BoNT/F L链和HN结构域；
iv.BoNT/F L链和HN结构域和非BoNT/F HC结构域；
v.BoNT/F L链和HC结构域和非BoNT/F HN结构域；或
vi.BoNT/F HN结构域和HC结构域和非BoNT/F L链。
例如，本发明的梭菌神经毒素(例如包含弗林蛋白酶切割位点的工程化梭菌神经毒素)可包含：
i.BoNT/G L链和非BoNT/G HN和HC结构域；
ii.BoNT/G HN结构域和非BoNT/G L链和HC结构域；
iii.BoNT/G HC结构域和非BoNT/G L链和HN结构域；
iv.BoNT/G L链和HN结构域和非BoNT/G HC结构域；
v.BoNT/G L链和HC结构域和非BoNT/G HN结构域；或
vi.BoNT/G HN结构域和HC结构域和非BoNT/G L链。
例如，本发明的梭菌神经毒素(例如包含弗林蛋白酶切割位点的工程化梭菌神经毒素)可包含：
i.BoNT/X L链和非BoNT/X HN和HC结构域；
ii.BoNT/X HN结构域和非BoNT/X L链和HC结构域；
iii.BoNT/X HC结构域和非BoNT/X L链和HN结构域；
iv.BoNT/X L链和HN结构域和非BoNT/X HC结构域；
v.BoNT/X L链和HC结构域和非BoNT/X HN结构域；或
vi.BoNT/X HN结构域和HC结构域和非BoNT/X L链。
例如，本发明的梭菌神经毒素(例如包含弗林蛋白酶切割位点的工程化梭菌神经毒素)可以包含：
i.TeNT L链和非TeNT HN和HC结构域；
ii.TeNT HN结构域和非TeNT L链和HC结构域；
iii.TeNT HC结构域和非TeNT L链和HN结构域；
iv.TeNT L链和HN结构域和非TeNT HC结构域；
v.TeNT L链和HC结构域和非TeNT HN结构域；或
vi.TeNT HN结构域和HC结构域和非TeNT L链。
术语“梭菌神经毒素”也可以包含由非梭菌微生物表达的新发现的肉毒神经毒素和肉毒神经毒素样蛋白家族成员，例如肠球菌编码的毒素，其与BoNT/X具有最接近的序列同一性，称为BoNT/Wo的Weissella oryzae编码的毒素(NCBI参考序列：WP_027699549.1)，其在W89-W90处裂解VAMP2，粪肠球菌编码的毒素(GenBank：OTO22244.1)，其裂解VAMP2和SNAP25，Chryseobacterium pipero编码的毒素(NCBI Ref.Seq：WP_034687872.1)和和蚊子BoNT样蛋白PMP1(NCBI Ref.Seq:QEZ70852.1)。。
术语“梭菌神经毒素”旨在包括重新靶向的梭菌神经毒素。在重新靶向的梭菌神经毒素中，梭菌神经毒素被修饰以包括称为靶向部分(TM)的外源性配体(即，不源自梭菌神经毒素)。选择TM以提供对所需靶细胞的结合特异性，并且作为重新靶向过程的一部分，可以去除梭菌神经毒素的天然结合部分(例如，HC结构域或HCC结构域)。重新靶向技术描述在，例如：EP-B-0689459；WO 1994/021300；EP-B-0939818；US 6,461,617；US 7,192,596；WO1998/007864；EP-B-0826051；US 5,989,545；US 6,395,513；US 6,962,703；WO 1996/033273；EP-B-0996468；US 7,052,702；WO 1999/017806；EP-B-1107794；US 6,632,440；WO2000/010598；WO 2001/21213；WO 2006/059093；WO 2000/62814；WO 2000/04926；WO 1993/15766；WO 2000/61192；和WO 1999/58571；所有内容通过引用整体并入本文。因此，本发明的梭菌神经毒素可以是重新靶向的梭菌神经毒素。特别地，本发明的工程化梭菌神经毒素可以是工程化的重新靶向的梭菌神经毒素。本发明的工程化的重新靶向的梭菌神经毒素可以包含在单链神经毒素的N-或C-末端呈现的TM，或者TM可以在单链神经毒素内的中心呈现。在一些优选的实施方案中，本发明的工程化的重新靶向的梭菌神经毒素可包含在单链神经毒素的N-或C-末端呈现的TM。
工程化的重新靶向的梭菌神经毒素可以允许使用易于被通常用于活化重组产生的重新靶向的梭菌神经毒素的蛋白酶(例如胰蛋白酶、Lys-C和/或BoNT水解酶)切割的TM。因此，与通过常规活化蛋白酶(如Lys-C、胰蛋白酶和/或BoNT水解酶)活化的相应的重新靶向的梭菌神经毒素相比，工程化的重新靶向的梭菌神经毒素以包含根据本发明的弗林蛋白酶活化位点可以允许稳定性的改善。
本发明的梭菌神经毒素(例如工程化梭菌神经毒素)可缺乏梭菌神经毒素的功能性HC结构域，并且还缺乏任何功能等同的TM。因此，所述多肽缺乏梭菌神经毒素的天然结合功能，并且在结合测定法中不能结合大鼠突触体膜(通过梭菌的HC组分，或通过任何功能上等效的TM)，如Shone等(1985)Eur.J.Biochem.151,75-82所述的。优选，TM不是小麦胚芽凝集素(WGA)肽。因此，在一些优选的实施方案中，梭菌神经毒素是重新靶向的梭菌神经毒素，其中梭菌神经毒素的内源性HC或HCC被外源性TM替代。特别优选的是其中工程化的梭菌神经毒素是重新靶向的梭菌神经毒素的实施方案，其中梭菌神经毒素的内源性HC或HCC被外源性TM替代。
本发明的梭菌神经毒素(例如工程化的梭菌神经毒素)可包含LHN多肽(例如工程化的LHN多肽)，即包含梭菌L链和梭菌HN结构域或由梭菌L链和梭菌梭菌HN结构域组成的多肽，如本文所定义。
梭菌神经毒素(例如工程化的梭菌神经毒素)可包含LHN多肽(例如工程化的LHN多肽)和靶向部分(TM)。
本发明还包括具有另外的非天然蛋白酶切割位点的梭菌神经毒素。这样的位点将需要外源性蛋白酶进行切割，这允许改善对切割事件的定时和位置的控制。可用于梭菌神经毒素的非天然蛋白酶切割位点包括：
TEV(烟草蚀纹病毒) (ENLYFQ↓G)(SEQ ID NO:65)
凝血酶 (LVPR↓GS)(SEQ ID NO:66)
PreScission (LEVLFQ↓GP)(SEQ ID NO:67)。
另外的蛋白酶裂解位点包括被非细胞毒性蛋白酶，例如被梭菌神经毒素的轻链裂解的识别序列。这些裂解位点包括被非细胞毒性蛋白酶，例如梭菌神经毒素的轻链裂解的SNARE(例如SNAP-25，突触融合蛋白，VAMP)蛋白识别序列。在US 7,132,259，EP 1206554-B2和US2007/0166332中描述了包含非天然蛋白酶裂解位点的梭菌神经毒素，其全部通过引用整体并入本文。术语蛋白酶裂解位点还包括内含肽，其是自裂解序列。例如，通过改变存在的还原剂的浓度，可控制自剪切反应。
本发明还涵盖包含“破坏性裂解位点”的梭菌神经毒素。在所述梭菌神经毒素中，将非天然蛋白酶裂解位点并入梭菌神经毒素中，选择并入的位置使得在所述位点处的裂解将降低梭菌神经毒素的活性或使其失活。如果在施用后梭菌神经毒素迁移至非靶标位置，则破坏性蛋白酶裂解位点可能易于被局部蛋白酶裂解。合适的非天然蛋白酶裂解位点包括上述那些。包含破坏性裂解位点的梭菌神经毒素描述于WO 2010/094905和WO 2002/044199中，这两个文献均通过引用整体并入本文。
本发明的梭菌神经毒素(例如工程化的梭菌神经毒素)，特别是其轻链组分可以被聚乙二醇化-这可以帮助增加稳定性，例如轻链组分的作用持续时间。当轻链包含BoNT/A、B或C1蛋白酶时，聚乙二醇化是特别优选的。聚乙二醇化优选包括将PEG添加至轻链组分的N-末端。举例来说，轻链的N-末端可以延伸一个或多个可以相同或不同的氨基酸(例如半胱氨酸)残基。一个或多个所述氨基酸残基可以具有其自身连接的PEG分子(例如，共价连接的)。在WO2007/104567中描述了该技术的示例，该申请的全部内容通过引用并入本文。
本发明的梭菌神经毒素(例如工程化的梭菌神经毒素)可以不含在天然存在的梭菌神经毒素复合物中存在的复合蛋白。
可以使用重组核酸技术生产本发明的梭菌神经毒素(例如工程化的梭菌神经毒素)。因此，工程化的梭菌神经毒素(如上所述)可以是重组工程化的梭菌神经毒素。单链梭菌神经毒素(如本文所述)可以是重组单链神经毒素。
与对相应的(工程化前)梭菌神经毒素的耐受性相比，对本发明的工程化梭菌神经毒素的耐受性可以增加。特别地，施用工程化前的梭菌神经毒素(例如以双链形式)时，与对相应的(工程化前的)梭菌神经毒素的耐受性相比，对本发明的工程化的梭菌神经毒素的耐受性可以增加。
与相应的(工程化前)梭菌神经毒素的效力相比，本发明的工程化梭菌神经毒素可具有等同或增加的效力。特别地，工程化前的梭菌神经毒素以双链形式施用时，与相应的(工程化前的)梭菌神经毒素的效力相比，本发明的工程化的梭菌神经毒素的效力可以等效或增加。如本文所用的术语“等效效力”意指工程化梭菌神经毒素具有相应(工程化前)梭菌神经毒素的效力的至少约80％、至少约85％、至少约90％、至少约95％、至少约99％、至多约100％的效力。优选，如本文所用的“等效效力”意指工程化梭菌神经毒素具有相应(工程化前)梭菌神经毒素的效力的至少约95％、至少约99％、至少约100％、至少约101％、至多约105％的效力。如本文所用的术语“增加的效力”意指工程化的梭菌神经毒素与相应的(工程化前)梭菌神经毒素的效力相比具有至少约10％、至少约15％、至少约20％、至少约25％更高的效力。可以使用任何适当的测定来测量效力，其常规实例在本文中描述。
与相应的(工程化前)梭菌神经毒素的安全性特征和/或治疗窗口相比，本发明的工程化梭菌神经毒素通常具有改善的安全性特征和/或治疗窗口。不受理论束缚，这可能是由于其改善的耐受性和/或等同或增加的效力。特别地，与施用(例如以双链形式)工程化前梭菌神经毒素时相应的(工程化前)梭菌神经毒素的安全性特征和/或治疗窗口相比，本发明的工程化梭菌神经毒素可具有改善的安全性特征和/或治疗窗口。
可以定义这些有利性质(其代表治疗指数的增加)的一种方式是根据工程化梭菌毒素的安全比(Safety Ratio)(对于临床应用)或耐受指数(Tolerance Index，TI，在动物模型中)。在这方面，不希望的梭菌神经毒素的作用(例如由神经毒素远离施用部位扩散引起的那些)可以通过测量相关动物模型(例如小鼠，其中在施用七天内检测到体重减轻)中的体重减轻百分比来实验评估。根据目的靶细胞，可以通过任何适当的技术实验评估梭菌毒素的期望的中靶效应。合适的测定法是本领域已知的，并且对于普通技术人员来说，为给定的靶细胞类型选择合适的测定法是常规的。对于靶向运动神经元的本发明的梭菌神经毒素，可以使用趾外展评分(DAS)测定(一种肌肉麻痹的测量)。DAS测定可以通过将配制在明胶磷酸盐缓冲液中的20μl(工程化)梭菌毒素注射到小鼠腓肠肌/比目鱼肌复合体中，然后使用Aoki的方法(Aoki KR,Toxicon 39：1815-1820；2001)评估趾外展评分来进行。在DAS测定中，通过尾巴短暂悬吊小鼠以引发特征性惊吓反应，其中小鼠伸展其后肢并外展其后趾。在梭菌毒素注射后，以五分制对不同程度的趾外展评分(0＝正常至4＝趾外展和腿伸展的最大减少)。对于靶向神经元的其他亚型的本发明的梭菌神经毒素，可以使用本领域已知的任何合适的测定法。SNARE切割测定也可用于评估本发明的工程化梭菌神经毒素的活性，其实例在本领域中充分描述(例如蛋白质印迹Western blot)。还可以使用检测和/或定量工程化梭菌神经毒素对标志物信号传导分子释放的影响的测定。可以根据工程化梭菌神经毒素靶向的细胞类型来选择特异性标志物信号分子。例如，信号传导分子可以是激素、P物质、CGRP、谷氨酸盐、甘氨酸，这取决于是否靶向了参与激素分泌的细胞或痛觉神经元。对于疼痛的治疗，可以使用动物研究来评估是否存在对有害刺激的更大耐受性。典型的体内测定将测量不同类型的疼痛(例如，机械、冷、热)，并且读数可以是行为的(例如，舔/咬处理部位或从有害刺激中撤出)或可能涉及使用Von Frey测试。可以使用任何合适的伤害感受测试，并且此类测试的实例是本领域熟知的。
梭菌神经毒素的安全比或TI然后可以表示为体重下降10％所需的毒素量(在小鼠给药后前七天内在峰值效应下测量)与DAS评分为2所需的毒素量之间的比率。因此，期望高安全比或TL评分，并且指示能够有效地使靶肌肉麻痹而几乎没有不期望的脱靶效应的毒素。本发明的工程化毒素可以具有高于等同的未修饰(工程化前)单链梭菌神经毒素的安全比和/或TI的安全比和/或TI。TI的计算可能根据所使用的实验模型而变化。
例如，在DAS小鼠模型中，本发明的工程化梭菌毒素具有至少8(例如，至少8、9、10、15、20、25、30、35、40、45或50)的TI，其中TI计算为：-10％体重变化所需的毒素剂量(pg/小鼠)除以DAS ED50(pg/小鼠)[ED50＝产生DAS评分2所需的剂量]
对于临床使用，可以计算安全比。
本发明提供了核酸(例如，DNA或RNA)，其包含编码如本文所述的梭菌神经毒素(例如工程化的梭菌神经毒素)的核酸序列。可以将核酸序列制备为表达载体的一部分，其中核酸与启动子可操作地连接。优选，可以将核酸制备为包含启动子和终止子的DNA表达载体的一部分。
优选，载体具有选自以下的启动子：
或者，启动子可以优选选自：
可以使用本领域已知的任何合适方法来制备本发明的核酸分子。因此，可以使用化学合成技术来制备核酸分子。或者，可以使用分子生物学技术来制备本发明的核酸分子。
本发明的核酸分子和表达载体可以优选在计算机上设计，然后通过常规合成技术(包括常规DNA合成技术)合成。
根据待采用的最终宿主细胞(例如大肠杆菌)表达系统，任选针对密码子偏好修饰上述核酸序列信息。
本发明提供了编码本发明的工程化梭菌神经毒素的核苷酸序列。本发明的核苷酸序列编码包含SEQ ID NO:1的弗林蛋白酶切割位点的多肽。
核苷酸序列可包含与SEQ ID NO:23具有至少70％序列同一性的序列。核苷酸序列可包含与SEQ ID NO:23具有至少80％或90％序列同一性的序列。优选，核苷酸序列包含SEQID NO:23(更优选由其组成)。核苷酸序列可以编码与SEQ ID NO:24或70至78中的一项或多项具有至少70％序列同一性的工程化梭菌神经毒素。核苷酸序列可以编码与SEQ ID NO:24或70至78中的一项或多项具有至少80％或90％序列同一性的工程化梭菌神经毒素。优选地，核苷酸序列编码工程化梭菌神经毒素，所述工程化梭菌神经毒素包含SEQ ID NO:24或70至78中的任一个(更优选由其组成)。
术语“核苷酸序列”和“核酸”和“多核苷酸”在本文中同义使用。优选地，核苷酸序列是DNA序列。
本发明提供了一种产生具有轻链和重链的单链(工程化)梭菌神经毒素蛋白的方法，该方法包括在合适的宿主细胞中表达本文所述的多核苷酸或表达载体，并回收表达的工程化梭菌神经毒素。回收表达的工程化梭菌神经毒素可包括裂解宿主细胞以提供含有单链(工程化)梭菌神经毒素蛋白的宿主细胞匀浆，和/或分离单链(工程化)梭菌神经毒素蛋白。所述方法可以进一步包括将本文所述的多核苷酸或表达载体引入宿主细胞中的步骤。合适的宿主细胞包括用于重组生产梭菌神经毒素的细菌细胞系，特别是大肠杆菌细胞。
本发明提供了一种将本发明的(工程化)梭菌神经毒素蛋白水解加工成相应的双链梭菌神经毒素的方法，所述方法包括使(工程化)梭菌神经毒素与弗林蛋白酶接触，从而产生双链梭菌神经毒素(例如其中轻链和重链通过二硫键连接在一起)。
因此，本发明提供了可通过本发明的方法获得的双链梭菌神经毒素。
如本文所用的术语“可获得的”还涵盖术语“获得的”。优选地，术语“可获得的”意指获得的。
工程化梭菌神经毒素的活化
本发明提供了一种将本发明的工程化梭菌神经毒素蛋白水解加工成相应的双链梭菌神经毒素的方法，所述方法包括使工程化梭菌神经毒素与弗林蛋白酶接触，从而产生双链梭菌神经毒素。所述接触可以是体外、离体或体内的，优选在体内。因此，本发明的治疗方法和用途可包括通过在靶细胞上或通过靶细胞的弗林蛋白酶表达在弗林蛋白酶活化位点处切割来体内活化本发明的工程化梭菌神经毒素。
因此，本发明的方法还可以包括使工程化梭菌神经毒素与弗林蛋白酶接触，从而产生相应的双链工程化梭菌神经毒素。优选地，所述接触在体内发生。
本发明还提供了一种用于将单链梭菌神经毒素蛋白水解加工成相应的双链梭菌神经毒素的方法，所述方法包括：(a)提供单链梭菌神经毒素；和(b)使单链梭菌神经毒素与弗林蛋白酶接触；其中所述单链梭菌神经毒素具有包含如本文所述的弗林蛋白酶切割位点(例如SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4或SEQ ID NO:5)或由其组成的活化环；并且其中弗林蛋白酶水解活化环的肽键，从而产生双链梭菌神经毒素。优选，所述接触在体内发生。
本发明包括使单链梭菌神经毒素(例如本发明的工程化梭菌神经毒素)与弗林蛋白酶接触，其中弗林蛋白酶能够水解单链梭菌神经毒素的活化环中的肽键，从而产生双链梭菌神经毒素。优选，所述接触在体内发生。
弗林蛋白酶是对一系列基序具有特异性的前体蛋白转化酶，切割由两个氨基酸分开的接近的配对的精氨酸残基。术语“弗林蛋白酶”涵盖本文所述的弗林蛋白酶，以及具有结构和/或功能相似性(优选结构和功能相似性)的能够水解SEQ ID NO:1的肽键的任何蛋白酶。合适的弗林蛋白酶是人弗林蛋白酶，其具有UniProt登录号P09958(序列的版本2，1990年4月1日保藏)。人弗林蛋白酶可从Merck商购获得(#F2677和#SRP6274)。对于体外和离体用途，确定弗林蛋白酶的适当浓度/单位量以在标准/所需条件下活化本发明的工程化梭菌神经毒素在本领域普通技术人员的常规实践范围内。
在本发明的上下文中，术语“弗林蛋白酶”涵盖与SEQ ID NO:59具有至少70％序列同一性的多肽序列。因此，“弗林蛋白酶”可包含与SEQ ID NO:59具有至少80％或90％序列同一性的多肽序列。优选，弗林蛋白酶包含SEQ ID NO:59(更优选由其组成)。
接触可以在任何合适的条件下发生，所述条件导致产生大于30％、40％、50％或60％(优选大于70％)的被蛋白水解加工成相应的双链梭菌神经毒素的单链梭菌神经毒素，而没有或基本上没有水解所述梭菌神经毒素的活化环外的肽键。“没有实质性水解”可以意指少于5％、4％、3％、2％或1％的接触的梭菌神经毒素在活化环外部含有在本发明的方法中被弗林蛋白酶水解的肽键。
技术人员可以选择适当的反应时间、温度、缓冲液和蛋白酶与单链梭菌神经毒素的摩尔比来实现上述目的。这些条件的优化可以使用常规技术凭经验确定，如SDS-PAGE(例如用考马斯或类似灵敏度的染料染色)，在所述接触或光谱技术(例如质谱法)后对反应产物进行视觉分析。
通过SDS-PAGE(例如用考马斯或类似灵敏度的染料染色)评估时，本发明的方法优选导致仅产生梭菌神经毒素L链和H链。
在本发明的方法中弗林蛋白酶的蛋白水解加工通常导致产生少于5种梭菌神经毒素L链或H链的降解产物，更优选少于4、3、2或1种降解产物。优选，通过本发明的方法产生的L链和H链是全长L链和H链。
优选，在本发明的方法中通过弗林蛋白酶加工仅水解紧邻SEQ ID NO:1的C-末端Arg的C-末端的肽键。
对于本发明的工程化梭菌神经毒素的体外弗林蛋白酶介导的活化，可以使用任何合适的活化条件。确定合适的条件在本领域普通技术人员的常规实践范围内。作为非限制性实例，每1mg工程化梭菌神经毒素可以使用15单位的弗林蛋白酶，活化在约25℃的温度下进行过夜。
许多细胞内源性地表达弗林蛋白酶，特别是在高尔基体和核质中。由细胞表达的弗林蛋白酶通常也存在于细胞表面上。因此，根据本发明的使梭菌神经毒素与弗林蛋白酶接触的步骤可以在用梭菌神经毒素处理的细胞表面处或附近发生。换句话说，根据本发明使梭菌神经毒素与弗林蛋白酶接触可涉及内源性存在于细胞表面的弗林蛋白酶。因此，根据本发明使梭菌神经毒素与弗林蛋白酶接触可以在向个体施用梭菌神经毒素后在体内发生。接触步骤在体内发生时，其通常涉及内源性存在于待根据本发明处理的组织或器官中存在的一个或多个细胞的表面处的弗林蛋白酶。
本发明还提供了可通过本发明的方法获得的双链梭菌神经毒素。由于双链形式的活化通过如本文所述的弗林蛋白酶切割位点处的切割而发生，因此所得的双链梭菌神经毒素的C-和N-末端切割末端与相应的(工程化前)梭菌神经毒素相比在序列上不同。作为非限制性实例，弗林蛋白酶对SEQ ID NO:24的工程化单链BoNT/A1的蛋白水解加工将产生具有以序列KKR结束的C-末端的LC和以STS开始的N-末端的HC的双链。相比之下，(工程化前)BoNT/A的常规胰蛋白酶切割将产生具有以序列TSK结束的C-末端的LC和以ALNDLC开始的N-末端的HC的双链。这些双链梭菌神经毒素可用于如本文所述的疗法中。除非另有说明，否则本文关于本发明的工程化或单链梭菌神经毒素的上下文中的治疗适应症和制剂的所有公开内容同样且不保留地适用于可通过本发明的方法获得的双链梭菌神经毒素。
单链梭菌神经毒素
梭菌神经毒素治疗领域中的共识是梭菌神经毒素在施用于患者之前必须被活化为其双链形式。活化可以通过具有必要切割特异性的常规活化蛋白酶，如Lys-C、胰蛋白酶和/或BoNT水解酶进行。与本领域中这种确定的偏见一致，迄今为止，单链梭菌神经毒素尚未用于治疗。
发明人还已经表明了尽管单链BoNT/A1在体内具有比天然双链BoNT/A1更低的活性，但它仍然能够引发治疗效果(如本文实施例中使用单链BoNT/A1引发的DAS评分所证明的)。这是令人惊讶的，因为本领域的常规观点是梭菌神经毒素需要以活性双链形式施用以在临床上有效。基于这些数据，发明人首次认识到单链梭菌神经毒素，如单链BoNT/A1具有治疗潜力，不需要在施用前活化成双链形式。
因此，本发明提供了梭菌神经毒素，其用于预防或治疗需要用肉毒神经毒素治疗的疾病或病症的方法中，其中梭菌神经毒素以单链形式施用于受试者。
本发明还提供了包含梭菌神经毒素的药物组合物用于预防或治疗适用肉毒神经毒素疗法的疾病或病症的方法，其中施用于受试者的药物组合物中的梭菌神经毒素是单链形式。
通常，用于此类方法的单链梭菌神经毒素或用于此类方法的包含所述单链梭菌神经毒素的药物组合物基本上不含双链形式的梭菌神经毒素。如本文所用，术语“基本上不含”可以定义为梭菌神经毒素或药物组合物包含小于400pg双链梭菌神经毒素/100ng单链梭菌神经毒素，或小于300pg双链梭菌神经毒素/100ng单链梭菌神经毒素，或小于200pg双链梭菌神经毒素/100ng单链梭菌神经毒素，或小于100pg双链梭菌神经毒素/100ng单链梭菌神经毒素，或小于50pg双链梭菌神经毒素/100ng单链梭菌神经毒素。基本上不含双链梭菌神经毒素的本发明的药物组合物可包含小于0.5％、小于0.4％、小于0.3％、小于0.2％、小于0.1％或小于0.05％的双链梭菌神经毒素，优选小于0.1％的双链梭菌神经毒素。
如本文实施例中所证明的，单链梭菌神经毒素通常不如相应梭菌神经毒素的双链形式有效(因为双链是活性形式)。作为非限制性实例，与相应的双链梭菌神经毒素相比，单链形式的梭菌神经毒素可具有至少30％、至少40％、至少50％、至少60％、至少70％、至少80％或更高的效力(特别是当单链和双链形式以相同剂量施用时)。作为进一步的非限制性实例，与相应的双链梭菌神经毒素相比，单链形式的梭菌神经毒素的效力可以低五倍、十倍或20倍(特别是当单链和双链形式以相同剂量施用时)。作为另一个非限制性实例，单链形式的梭菌神经毒素与相应的双链梭菌神经毒素相比(特别是当单链和双链形式存在时)，达到半最大麻痹的时间可以长至少25％、至少50％、至少60％、至少70％、至少80％、至少85％、至少90％、至少95％、至少96％、至少97％、至少98％、至少99％或更长。可以使用任何适当的测定来测量效力，其常规实例在本文中描述。
无论相同梭菌神经毒素的单链和双链形式之间的效力是否有任何差异，相对于相同梭菌神经毒素的双链形式的治疗剂量，使用增加剂量的单链梭菌神经毒素可以潜在地实现相同的治疗效果。单链梭菌神经毒素可以以相应双链梭菌神经毒素剂量的至少2倍(2×)、至少3×、至少4×、至少5×、至少10×、至少15×、至少20×的剂量使用。
与使用相应的双链梭菌神经毒素相比，使用单链形式的梭菌神经毒素提供了几个潜在的优点。与施用相应的双链梭菌神经毒素相比，施用单链形式的梭菌神经毒素产生更少和/或不太严重的副作用，特别是如果以相同剂量施用。
使用单链梭菌神经毒素的另一个潜在优点是单链梭菌神经毒素的GMP生产以产生临床上可接受的药物/美容组合物将更容易和更便宜。这是因为通常用于在生产过程期间和施用之前将单链梭菌神经毒素切割成活性双链形式的蛋白酶是显著的试剂成本，并且因此去除对所述蛋白酶的需要将降低制造成本。此外，常规制造方案必然涉及一个或多个另外的纯化步骤以从活化蛋白酶中纯化双链梭菌神经毒素。如果在施用前不需要活化，因此在制造过程中不需要使用蛋白酶，则也可以省略这些额外的纯化步骤，进一步降低成本、制造过程的复杂性和生产时间。
本发明还提供了包含单链梭菌神经毒素和美容上可接受的载体、赋形剂、稀释剂、佐剂、推进剂和/或盐的美容组合物的用途，用于预防或减轻指示应用肉毒神经毒素的美容适应症，其中单链梭菌神经毒素以单链形式施用于受试者。
根据本发明的用于用途的单链梭菌神经毒素通常被存在于受试者体内的内源性蛋白酶切割以产生活性双链梭菌神经毒素。通常，受试者的靶细胞表达内源性蛋白酶，其将单链梭菌神经毒素活化成双链形式。因此，根据本发明施用于受试者的单链梭菌神经毒素的活化通常在向受试者施用单链梭菌神经毒素后在体内发生。一种或多种蛋白酶通常内源性地存在于待根据本发明处理的组织或器官中存在的一种或多种细胞中。
除非另有明确说明，否则本文关于梭菌神经毒素的任何和所有公开内容同样适用于本发明的涉及用单链梭菌神经毒素治疗受试者的方面，且没有保留。作为非限制性实例，本发明涉及用单链梭菌神经毒素治疗受试者，所述单链梭菌神经毒素是任何BoNT血清型，特别是BoNT/A，优选BoNT/A1的单链形式。本文描述了示例性BoNT序列，特别是BoNT/A，甚至更特别是BoNT/A1。作为另一个非限制性实例，本发明涉及用单链梭菌神经毒素治疗受试者，所述单链梭菌神经毒素是单链形式的重新靶向的梭菌神经毒素、嵌合梭菌神经毒素、杂合梭菌神经毒素或其任何片段或变体，如本文所述。
治疗和制剂
本发明的梭菌神经毒素适当地发现了在医药和/或美容中的实用性。在使用中，由于本发明的工程化梭菌神经毒素可以通过如本文所述的弗林蛋白酶在体内切割，梭菌神经毒素优选为用于施用的单链形式。或者，本发明的工程化梭菌神经毒素可以以双链形式施用(例如通过本发明的方法获得)。
本发明的(工程化)梭菌神经毒素可用于预防或治疗某些医学或美容疾病和病症。因此，在另一方面中，本发明提供了如上所述的(工程化)梭菌神经毒素，用于医学中。此外，如本文所述，本发明涉及单链梭菌神经毒素，其用于预防或治疗某些医学或美容疾病和病症，其中将单链梭菌神经毒素施用于受试者。此外，如本文所述，本发明涉及可通过本发明的方法获得的双链梭菌神经毒素，其用于预防或治疗某些医学或美容疾病和病症，其中将可通过本发明的方法获得的双链梭菌神经毒素施用于受试者。因此，在另一方面中，本发明提供了如上所述的(工程化)梭菌神经毒素，用于医学中。
因此，本发明提供了如上所述的梭菌神经毒素(例如工程化梭菌神经毒素)，其用于预防或治疗选自以下的疾病或病症：与不合需要的免疫分泌相关的病症、斜视(strabismus)、眼睑痉挛、斜视(squint)、肌张力障碍(例如痉挛性肌张力障碍、口下颌肌张力障碍，局灶性肌张力异常、迟发性肌张力不良、喉部肌张力障碍和肢体肌张力障碍以及颈颈肌张力障碍)、斜颈(例如痉挛型斜颈)、受益于细胞/肌肉丧失能力(经由SNARE下调或失活)的美容治疗(美容)应用、眼运动的神经肌肉紊乱或病况(如伴行斜视、垂直斜视、侧直肌麻痹、眼球震颤、甲状腺功能异常肌病)、作家痉挛、磨牙症、Wilson病、震颤、抽搐、节段性肌阵挛、痉挛，由于慢性多发性硬化症引起的痉挛、导致膀胱控制异常的痉挛、男性意像(animus)、背部痉挛、抽筋、骨盆提肌综合征(levator pelvic syndrome)、脊柱裂、迟发性运动障碍、帕金森病、口吃、面肌痉挛、眼睑障碍、脑瘫、局灶性痉挛、痉挛性结肠炎、神经源性膀胱、盆底失弛缓综合征(anismus)、肢体僵直(limb spasticity)、抽动、震颤、磨牙症、肛裂、贲门失弛缓症、吞咽困难、流泪、多汗症、唾液过多、胃肠道分泌物过多、肌肉疼痛(如肌肉痉挛引起的疼痛)、头痛(如紧张性头痛或偏头痛)、幻痛(例如，幻肢痛)、眉沟、皮肤皱纹、癌症、子宫疾病、泌尿生殖器病症、泌尿生殖神经系统疾病、膀胱疼痛综合征、间质性膀胱炎、慢性神经源性炎症和平滑肌障碍。在一些情况下，病症可以选自幻痛(例如幻肢痛)和膀胱疼痛综合征。类似地，本发明还涉及可通过本发明的方法获得的单链梭菌神经毒素和双链梭菌神经毒素，其用于治疗或预防上述疾病或病症。
本发明的梭菌神经毒素(例如工程化梭菌神经毒素)包含BoNT/X序列(或其部分)时，由于其切割VAMP4、VAMP5和/或Ykt6的能力，所述梭菌神经毒素可能能够靶向除神经元以外的其他类型的分泌细胞。在一些实施方案中，靶向的分泌细胞是分泌免疫细胞。如本文所用，“分泌免疫细胞”是指分泌细胞因子、趋化因子或抗体的免疫细胞。此类分泌免疫细胞可以是固有免疫细胞，包括但不限于天然杀伤细胞、肥大细胞、嗜酸性粒细胞、嗜碱性粒细胞、巨噬细胞、嗜中性粒细胞和树突细胞。分泌抗体的分泌免疫细胞(例如白细胞)也可以被本发明的梭菌神经毒素靶向。抗体分泌细胞的非限制性示例包括但不限于血浆B细胞、浆细胞(plasmocytes)、浆细胞(plasmacytes)和效应B细胞。在一些实施方案中，梭菌神经毒素可调节免疫应答。因此，本文进一步考虑了本发明的梭菌神经毒素在治疗与不想要的分泌，优选与不想要的免疫分泌相关的病症中的治疗用途。与不想要的免疫分泌相关的病症包括但不限于：炎症、牛皮癣、过敏、噬血细胞淋巴组织细胞增生和酒精性胰腺疾病。
本发明还提供了如上所述的梭菌神经毒素(例如可通过本发明的方法获得的工程化梭菌神经毒素、单链梭菌神经毒素或双链梭菌神经毒素)在制备用于预防或治疗如本文所述的疾病或病症的方法中的药物中的用途。
本发明还提供了一种治疗如本文所述的疾病或病症的方法，所述方法包括向有需要的受试者施用治疗有效量的如上所述的梭菌神经毒素(例如通过本发明的方法可获得的工程化梭菌神经毒素、单链梭菌神经毒素或双链梭菌神经毒素).
本发明提供药物组合物，其包含本发明的(工程化)梭菌神经毒素或双链梭菌神经毒素和药学上可接受的载体、赋形剂、佐剂、推进剂和/或盐。优选，(工程化)梭菌神经毒素是单链形式(例如经工程化以包含弗林蛋白酶切割位点)。
本发明还提供美容组合物，其包含本发明的(工程化)梭菌神经毒素或本发明的双链梭菌神经毒素和美容上可接受的载体、赋形剂、稀释剂、佐剂、推进剂和/或盐。本发明还提供了包含梭菌神经毒素(例如可通过本发明的方法获得的工程化梭菌神经毒素、单链梭菌神经毒素或双链梭菌神经毒素)的美容组合物用于预防或减轻需要应用肉毒神经毒素的美容适应症的用途。本发明还提供了包含梭菌神经毒素(例如可通过本发明的方法获得的工程化梭菌神经毒素、单链梭菌神经毒素或双链梭菌神经毒素)的美容组合物用于预防或减轻适用应用肉毒神经毒素的美容适应症的用途。优选地(工程化)梭菌神经毒素是单链形式(例如工程化以包含弗林蛋白酶切割位点)。
本发明的梭菌神经毒素(例如工程化梭菌神经毒素)可以配制用于口服、肠胃外、持续输注、吸入或局部应用。适合注射的组合物可以是溶液、悬浮液或乳液或干粉的形式，所述干粉在使用前溶解或悬浮在合适的溶媒中。
在待局部递送的梭菌神经毒素(例如工程化梭菌神经毒素)的情况下，梭菌神经毒素(例如工程化梭菌神经毒素)可以配制成乳膏(例如用于局部应用)或用于皮下注射。
局部递送装置可包括气溶胶或其他喷雾剂(例如喷雾器)。在这方面，梭菌神经毒素(例如工程化梭菌神经毒素)的气溶胶制剂能够递送至肺和/或其他鼻和/或支气管或气道通道。
本发明的梭菌神经毒素(例如工程化的梭菌神经毒素)可以通过鞘内或硬膜外注射，在涉及受影响器官的神经分布的脊柱节段的水平，在脊柱内施用于患者。
优选的施用途径是通过腹腔镜和/或局部注射，特别是肌内注射施用。
本发明的(工程化的)梭菌神经毒素的施用剂量范围是产生期望的治疗效果的剂量范围。应当理解，所需的剂量范围取决于(工程化的)梭菌神经毒素或组合物的确切性质、施用途径、制剂性质、患者的年龄、患者病症的性质、程度或严重性、禁忌症(如果有)和主治医师的判断。可以使用优化的标准经验程序调整这些剂量水平的变化。
合适的日剂量(每千克患者体重)在0.0001-1ng/kg的范围内，优选0.0001-0.5ng/kg，更优选0.002-0.5ng/kg，特别优选0.004-0.5ng/kg。单位剂量可以从少于1皮克到30ng不等，但通常在每剂0.01ng到1ng的范围内，可以每天施用，或优选以更低的频率施用，例如每周、每月或每六个月施用。
一种特别优选的给药方案是基于0.05ng(工程化的)梭菌神经毒素作为1X剂量。在这方面，优选剂量范围是1X–100X(即0.05-5ng)。
通常利用梭菌神经毒素(例如工程化梭菌神经毒素)和无热原的无菌介质制备流体剂型。根据所用的溶媒和浓度，梭菌神经毒素(例如工程化梭菌神经毒素)可以溶解或悬浮在溶媒介质中。在制备溶液时，可以将梭菌神经毒素(例如工程化梭菌神经毒素)溶解在溶媒介质中，如有必要，可通过添加氯化钠使溶液等渗，并使用无菌技术通过无菌过滤器过滤灭菌，然后填充到合适的无菌小瓶或安瓿瓶中并密封。或者，如果溶液的稳定性足够，则可以通过高压灭菌对密封容器中的溶液进行灭菌。有利地，可以将添加剂溶解在载剂中，所述添加剂例如为缓冲剂、增溶剂、稳定剂、防腐剂或杀菌剂、助悬剂或乳化剂和/或局部麻醉剂。
通过使用无菌技术在无菌区域将预先灭菌的成分填充到无菌容器中，可以制备干粉，以在使用前溶解或悬浮在合适的载剂中。可替代地，可以使用无菌技术在无菌区域中将成分溶解到合适的容器中。然后将产品冷冻干燥，并将容器无菌密封。
以基本上相同的方式制备适合于肌内、皮下或皮内注射的肠胃外混悬剂，不同之处在于将无菌组分悬浮在无菌载剂体中，而不是溶解，并且不能通过过滤来实现灭菌。可以以无菌状态分离组分，或者可选地，可以在分离后例如通过γ辐射将其灭菌。
有利地，在一种或多种组合物中包括助悬剂，例如聚乙烯吡咯烷酮，以促进组分的均匀分布。
根据本发明的施用可以利用多种递送技术，包括微粒包封、病毒递送系统或高压喷雾撞击。
与本发明的各种方法相关的公开内容旨在同样地应用于其他方法、梭菌神经毒素，例如工程化梭菌神经毒素(无论是单链还是双链形式)、用途或药物组合物，以及单链梭菌神经毒素的医学用途，反之亦然。
序列同源性
多种序列比对方法中的任何都可以用于确定同一性百分比，包括但不限于全局方法、局部方法和混合方法，如，例如区段方法。确定同一性百分比的方案是本领域技术人员范围内的常规程序。全局方法从分子的开始到结束比对序列，并通过累加各个残基对的分数和通过施加空位罚分来确定最佳比对。非限制性方法包括，例如CLUSTAL W，参见例如Julie D.Thompson等，CLUSTAL W:Improving the Sensitivity of ProgressiveMultiple Sequence Alignment Through Sequence Weighting,Position-Specific GapPenalties and Weight Matrix Choice,22(22)Nucleic Acids Research 4673-4680(1994)；和迭代改进，参见例如，Osamu Gotoh,Significant Improvement in Accuracy ofMultiple Protein Sequence Alignments by Iterative Refinement as Assessed byReference to Structural Alignments,264(4)J.MoI.Biol.823-838(1996)。局部方法通过鉴定所有输入序列共有的一个或多个保守基序来比对序列。非限制性方法包括，例如火柴盒(Match-box)，参见例如Eric Depiereux and Ernest Feytmans,Match-Box:AFundamentally New Algorithm for the Simultaneous Alignment of Several ProteinSequences,8(5)CABIOS 501 -509(1992)；Gibbs采样，参见例如C.E.Lawrence等，Detecting Subtle Sequence Signals:A Gibbs Sampling Strategy for MultipleAlignment,262(5131)Science 208-214(1993)；Align-M，参见，例如，Ivo Van WaIIe等，Align-M-A New Algorithm for Multiple Alignment of Highly Divergent Sequences,20(9)Bioinformatics:1428-1435(2004)。
因此，通过常规方法确定序列同一性百分比。参见，例如，Altschul等，Bull.Math.Bio.48:603-16，1986以及Henikoff和Henikoff,Proc.Natl.Acad.Sci.USA 89:10915-19，1992。简而言之，如下所示，使用空位开放罚分10，空位延伸罚分1，以及Henikoff和Henikoff的“blosum 62”评分矩阵(同上)对两个氨基酸序列进行比对，以优化比对得分(氨基酸由标准的单字母代码表示)。
两个或更多个核酸或氨基酸序列之间的“序列同一性百分比”是该序列共有的相同位置数目的函数。因此，同一性％可以计算为相同核苷酸/氨基酸的数目除以核苷酸/氨基酸的总数，再乘以100。％序列同一性的计算也可以考虑需要引入以优化两个或更多个序列比对的空位的数目，以及每个空位的长度。可以使用本领域技术人员熟悉的特定数学算法(如BLAST)进行序列比较和确定两个或多个序列之间的同一性百分比。
确定序列同一性的比对得分
然后将同一性百分比计算为：
基本上同源的多肽的特征在于具有一个或多个氨基酸取代、删除或添加。这些变化优选是不重要的，即，保守的氨基酸取代(见下文)和不显著影响多肽折叠或活性的其他取代；小的删除，通常1至约30个氨基酸；和小的氨基或羧基末端延伸，如氨基末端甲硫氨酸残基，最多约20-25个残基的小接头肽或亲和标签。
保守性氨基酸取代
碱性：精氨酸
赖氨酸
组氨酸
酸性：谷氨酸
天冬氨酸
极性：谷氨酰胺
天冬酰胺
疏水性：亮氨酸
异亮氨酸
缬氨酸
芳香族：苯丙氨酸
色氨酸
酪氨酸
小的：甘氨酸
丙氨酸
丝氨酸
苏氨酸
甲硫氨酸
除20种标准氨基酸外，非标准氨基酸(如4-羟基脯氨酸、6-N-甲基赖氨酸、2-氨基异丁酸、异缬氨酸和α-甲基丝氨酸)可以取代本发明多肽的氨基酸残基。有限数量的非保守氨基酸、不是由遗传密码子编码的氨基酸和非天然氨基酸可以取代多肽氨基酸残基。本发明的多肽还可以包含非天然存在的氨基酸残基。
非天然存在的氨基酸包括但不限于，反式-3-甲基脯氨酸、2,4-甲基-脯氨酸、顺式-4-羟基脯氨酸、反式-4-羟基脯氨酸、N-甲基甘氨酸、别苏氨酸、甲基苏氨酸、羟乙基半胱氨酸、羟乙基高半胱氨酸、硝基谷氨酰胺、高谷氨酰胺、哌啶酸、叔亮氨酸、正缬氨酸、2-氮杂苯丙氨酸、3-氮杂苯丙氨酸、4-氮杂苯丙氨酸和4-氟苯丙氨酸。用于将非天然存在的氨基酸残基并入蛋白质中的几种方法是本领域已知的。例如，可以使用体外系统，其中使用化学氨酰化的抑制子tRNA抑制无义突变。合成氨基酸和氨酰化tRNA的方法是本领域已知的。包含无义突变的质粒的转录和翻译是在无细胞系统中进行的，该系统包含大肠杆菌S30提取物以及可商购的酶和其他试剂。蛋白质通过色谱法纯化。参见，例如，Robertson等，J.Am.Chem.Soc.113:2722,1991；Ellman等，Methods Enzymol.202:301，1991；Chung等，Science 259:806-9，1993和Chung等，Proc.Natl.Acad.Sci.USA90:10145-9，1993)。在第二种方法中，通过显微注射突变的mRNA和化学氨酰化的抑制子tRNA在非洲爪蟾卵母细胞中进行翻译(Turcatti等，J.Biol.Chem.271:19991-8，1996)。在第三种方法中，在不存在待替代的天然氨基酸(例如，苯丙氨酸)和存在期望的非天然存在的氨基酸(例如，2-氮杂苯丙氨酸、3-氮杂苯丙氨酸、4-氮杂苯丙氨酸或4-氟苯丙氨酸)的情况下培养大肠杆菌细胞。将非天然存在的氨基酸并入多肽中，代替其天然对应物。参见，Koide等，Biochem.33:7470-6，1994。可通过体外化学修饰将天然存在的氨基酸残基转化为非天然存在的物质。化学修饰可以与定点诱变组合使用，以进一步扩大取代范围(Wynn和Richards，Protein Sci.2:395-403，1993)。
有限数量的非保守氨基酸、不是由遗传密码子编码的氨基酸、非天然存在的氨基酸和非天然氨基酸可以取代本发明多肽的氨基酸残基。
可以根据本领域已知的程序来鉴定本发明多肽中的必需氨基酸，如定点诱变或丙氨酸扫描诱变(Cunningham和Wells，Science 244:1081-5，1989)。也可以通过结构的物理分析来确定生物相互作用的位点，如通过核磁共振、晶体学、电子衍射或光亲和标记等技术，结合假定的接触位点氨基酸突变来确定。参见，例如，de Vos等，Science 255:306-12，1992；Smith等，J.Mol.Biol.224:899-904，1992；Wlodaver等，FEBS Lett.309:59-64，1992。还可以从与本发明多肽的相关组分(例如易位或蛋白酶组分)的同源性分析中推断出必需氨基酸的鉴定。
可以使用诱变和筛选的已知方法进行多种氨基酸取代，并进行测试，例如Reidhaar-Olson和Sauer(Science 241:53-7，1988)或Bowie和Sauer(Proc.Natl.Acad.Sci.USA86:2152-6，1989)中公开的那些方法。简而言之，这些作者公开了同时使多肽中的两个或更多个位置随机化，选择功能性多肽，然后对诱变的多肽进行测序以确定每个位置上允许取代的光谱的方法。可以使用的其他方法包括噬菌体展示(例如，Lowman等，Biochem.30:10832-7，1991；Ladner等，美国专利号5,223,409；Huse，WIPO公开WO92/06204)和区域定向诱变(Derbyshire等，Gene 46:145，1986；Ner等，DNA7:127，1988)。
序列信息
在任何以下SEQ ID NO中指示起始Met氨基酸残基或相应的起始密码子时，所述残基/密码子是任选的。
SEQ ID NO:1(弗林蛋白酶切割位点共有序列)
SEQ ID NO:2(弗林蛋白酶切割位点共有序列)
SEQ ID NO:3(弗林蛋白酶切割位点共有序列)
SEQ ID NO:4(弗林蛋白酶切割位点)
SEQ ID NO:5(弗林蛋白酶切割位点)
SEQ ID NO:6(弗林蛋白酶切割位点)
SEQ ID NO:7(弗林蛋白酶切割位点)
SEQ ID NO:8(弗林蛋白酶切割位点)
SEQ ID NO:9(弗林蛋白酶切割位点)
SEQ ID NO:10(弗林蛋白酶切割位点)
SEQ ID NO:11(弗林蛋白酶切割位点)
SEQ ID NO:12(弗林蛋白酶切割位点)
SEQ ID NO:13(弗林蛋白酶切割位点)
SEQ ID NO:14(基于具有弗林蛋白酶切割位点的BoNT/A1活化环的外源性活化环)
SEQ ID NO:15(基于具有弗林蛋白酶切割位点的BoNT/A1活化环的外源性活化环)
SEQ ID NO:16(基于具有弗林蛋白酶切割位点的BoNT/A1活化环的外源性活化环)
SEQ ID NO:17(基于具有弗林蛋白酶切割位点的BoNT/A1活化环的外源性活化环)
SEQ ID NO:18(基于具有弗林蛋白酶切割位点的BoNT/A1活化环的外源性活化环)
SEQ ID NO:19(基于具有弗林蛋白酶切割位点的BoNT/A1活化环的外源性活化环)
SEQ ID NO:20(基于具有弗林蛋白酶切割位点的BoNT/A1活化环的外源性活化环)
SEQ ID NO:21(基于具有弗林蛋白酶切割位点的BoNT/A1活化环的外源性活化环)
SEQ ID NO:22(基于具有弗林蛋白酶切割位点的BoNT/A1活化环的外源性活化环)
SEQ ID NO:23(具有弗林蛋白酶切割位点的BoNT/A1的核酸序列)
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SEQ ID NO:24(具有弗林蛋白酶切割位点的BoNT/A1的氨基酸序列)
外源弗林蛋白酶切割位点(下划线的)替代内源性BoNT/A1活化环(粗体)的一部分。
SEQ ID NO:25(BoNT/A-UniProt P10845)
在一些实施方案中，缬氨酸27可以被丙氨酸取代，如SEQ ID NO:68中所示。
SEQ
ID
NO:26(BoNT/B-Uniprot P10844)
SEQ ID NO:27(BoNT/C-Uniprot P18640)
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SEQ ID NO:28(BoNT/D-Uniprot P19321)
SEQ ID NO:29(BoNT/E-Uniprot Q00496)
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SEQ ID NO:30(BoNT/F-Uniprot A7GBG3)
SEQ ID NO:31(BoNT/G-Uniprot Q60393)
SEQ ID NO:32(BoNT/X的多肽序列)
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SEQ ID NO:33(TeNT-Uniprot P04958)
SEQ ID NO:34(BoNT/D活化环)
SEQ ID NO:35(BoNT/DC活化环)
SEQ ID NO:36(BoNT/C1和CD活化环)
SEQ ID NO:37(BoNT/A4活化环)
SEQ ID NO:38(BoNT/A5和A7活化环)
SEQ ID NO:39(BoNT/A1和A6活化环)
SEQ ID NO:40(BoNT/A3活化环)
SEQ ID NO:41(BoNT/A2和A8活化环)
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SEQ ID NO:42(BoNT/H活化环)
SEQ ID NO:43(BoNT/E1至E5、E9和E12活化环)
SEQ ID NO:44(BoNT/E11活化环)
SEQ ID NO:45(BoNT/E7、E8和E10活化环)
SEQ ID NO:46(BoNT/E6活化环)
SEQ ID NO:47(BoNT/F7活化环)
SEQ ID NO:48(BoNT/F5活化环)
SEQ ID NO:49(BoNT/F1和F6活化环)
SEQ ID NO:50(BoNT/F4活化环)
SEQ ID NO:51(BoNT/F2和F3活化环)
SEQ ID NO:52(TeNT活化环)
SEQ ID NO:53(BoNT/G活化环)
SEQ ID NO:54(BoNT/B4活化环)
SEQ ID NO:55(BoNT/B2、B3、B6和B8活化环)
SEQ ID NO:56(BoNT/B1、B5和B7活化环)
SEQ ID NO:57(BoNT/X活化环)
SEQ ID NO:58金属配位SNARE切割基序
SEQ ID NO:59(人弗林蛋白酶的氨基酸序列)
SEQ ID NO:60(另外的蛋白酶切割位点)
x是任何氨基酸
SEQ ID NO:61(另外的蛋白酶切割位点)
x是任何氨基酸
SEQ ID NO:62(另外的蛋白酶切割位点)
x是任何氨基酸
SEQ ID NO:63(另外的蛋白酶切割位点)
x是任何氨基酸
SEQ ID NO:64(另外的蛋白酶切割位点)
x是任何氨基酸；Hy是疏水性氨基酸
SEQ ID NO:65(TEV切割位点)
SEQ ID NO:66(凝血酶切割位点)
SEQ ID NO:67(PreScission切割位点)
SEQ ID NO:68(BoNT/A)
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SEQ ID NO:69:非工程化BoNT/AB嵌合体
SytII结合突变E1191M和S1199Y由粗体和下划线标出。
内源性活化环由虚线标出。
SEQ ID NO:70:工程化的BoNT/AB嵌合体
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SytII结合突变E1191M和S1199Y由粗体和下划线标出。
外源性弗林蛋白酶切割位点(下划线的)替代内源性BoNT/A1活化环(粗体)的一部分。
SEQ ID NO:71衍生自SEQ ID NO:26的工程化BoNT/B
外源性弗林蛋白酶切割位点(下划线的)替代内源性BoNT/B活化环(粗体)的一部分。
SEQ ID NO:72衍生自SEQ ID NO:27的工程化BoNT/C
外源弗林蛋白酶切割位点(下划线的)替代内源性BoNT/C活化环(粗体)的一部分。
SEQ ID NO:73衍生自SEQ ID NO:28的工程化BoNT/D
外源性弗林蛋白酶切割位点(下划线的)替代内源性BoNT/D活化环(粗体)的一部分。
SEQ ID NO:74衍生自SEQ ID NO:29的工程化BoNT/E
外源性弗林蛋白酶切割位点(下划线的)替代内源性BoNT/E活化环(粗体)的一部分。
SEQ ID NO:75衍生自SEQ ID NO:30的工程化BoNT/F
外源性弗林蛋白酶切割位点(下划线的)替代内源性BoNT/F活化环(粗体)的一部分。
SEQ ID NO:76衍生自SEQ ID NO:31的工程化BoNT/G
外源性弗林蛋白酶切割位点(下划线的)替代内源性BoNT/G活化环(粗体)的一部分。
SEQ ID NO:77衍生自SEQ ID NO:32的工程化BoNT/X
外源性弗林蛋白酶切割位点(下划线的)替代内源性BoNT/X活化环(粗体)的一部分。
SEQ ID NO:78衍生自SEQ ID NO:32的工程化BoNT/X
外源性弗林蛋白酶切割位点(下划线的)替代内源性BoNT/X活化环(粗体)的一部分。
实施例
本发明将通过以下实施例进一步阐明，这些实施例旨在纯粹举例说明本发明，而决不是限制性的。
实施例1-内源性活化环被弗林蛋白酶切割位点替换的BoNT/A1的设计和产生
修饰SEQ ID NO:68的BoNT/A1以将活化环的一部分(SEQ ID NO:25的氨基酸残基435-448)替换为弗林蛋白酶切割位点(SEQ ID NO:5)，产生工程化BoNT/A1-弗林蛋白酶蛋白质SEQID NO:24(SXN104539)。通过使用成对寡核苷酸通过常规取代诱变用所需的弗林蛋白酶序列替换编码SEQ ID NO:25的质粒中的活化环中的密码子来创建编码SEQ ID NO:24的DNA构建体。靶蛋白(SXN104539)在大肠杆菌BL21 DE3细胞中表达，并在裂解后使用经典色谱技术纯化。这涉及通过疏水性相互作用色谱的初始捕获步骤，然后是阴离子交换色谱和缓冲液交换到PBS pH 7.2中。
1.2μg SXN 104539与1μg弗林蛋白酶在24μL中在25℃下温育48h，并在DTT存在或不存在(分别为还原或非还原的)下通过SDS-PAGE解析样品(图2)。该凝胶证实了～50kDa和通过二硫键连接的～100kDa链的存在，而还原的人弗林蛋白酶表现为在～60kDa处的条带。通过蛋白质印迹证实～50kDa条带是LC/A(图2)。
实施例2-BoNT/A1-弗林蛋白酶与天然BoNT/A1和重组BoNT/A1的效力比较
使用大鼠胚胎脊髓神经元(eSCN)评估工程化BoNT/A1-弗林蛋白酶(SXN104539进入神经元并切割SNAP-25(BoNT/A1的靶标)的能力。图3显示SXN104539显示了与天然BoNT/A1(LIST，其主要为双链形式)相比相同的pEC50，但单链重组BoNT/A1(scSXN104445)的效力低1.3log单位(20×)。
因此，这些结果表明，SXN104539保留了与天然BoNT/A1相同的进入神经元和切割SNAP-25的能力，并且与单链BoNT/A1(scSXN104445)相比具有改善的效力。
使用小鼠膈神经半膈肌测定(mPNHD)进一步评估SXN104539的效力。图4显示具有弗林蛋白酶环的单链rBoNT/A(SXN104539)与重组BoNT/A双链(SXN102342)等效(p>0.05 1wANOVA)。
| t50(平均值±sem),n＝3 | |
| rBoNT/A scSXN104445 | 77±3min |
| rBoNT/A(弗林蛋白酶)sc SXN104539 | 40±1min |
| rBoNT/A dcSXN102342 | 42±2min |
这些效力结果证明用弗林蛋白酶切割位点替换梭菌神经毒素内源性活化环是梭菌神经毒素的体内活化的成功策略。
实施例3-对BoNT/A1-弗林蛋白酶、天然BoNT/A1、重组双链BoNT/A1和重组单链BoNT/A1的
耐受性的比较
使用体内小鼠趾外展评分(DAS)测定来评估相对于天然BoNT/A1和rBoNT/A1的效力以及安全性。
从5pg/小鼠i.m.可观察到体重(BW)降低(图5A)。5μg/小鼠i.m.的BW损失。测试的所有分子在5pg/小鼠i.m.下BW损失，并且对于nBoNT/A1和scSXN104445，D1 BW降低最大并在D3恢复(达到MTD)。对于SXN104539，在D3观察到最大BW降低，但耐受性良好(体重降低小于10％)。
在较长时间的第二个实验中，与重组BoNT/A1双链相比，具有弗林蛋白酶环的单链rBoNT/A(SXN104539)对BW的影响较小(图5B)，表明SXN104539可能比重组BoNT/A1双链更好地被耐受。
对于5pg/小鼠的scSXN104445或nBoNT/A1(该剂量的nBoNT/A1诱导了BW降低)，在四天时间过程t内未达到DAS 4。按量级的DAS评分为SXN104539>nBoNT/A1>scSXN104445(图6)。
还评估了作用持续时间。测试了较低剂量(4pg/小鼠)并确定了DAS评分。对于dcrBoNT/A1和SXN104539均实现了DAS 4。图7显示了所有测试分子的作用持续时间为dcrBoNT/A1>SXN104539>sc rBoNT/A1。
上述说明书中提及的所有出版物均通过引用并入本文。在不脱离本发明的范围和精神的情况下，本发明的所述方法和系统的各种修改和变化对于本领域技术人员将是显而易见的。尽管已经结合具体的优选实施方案描述了本发明，但是应当理解，所要求保护的本发明不应不适当地限于这些具体实施方案。实际上，对于生物化学和生物技术或相关领域的技术人员显而易见的用于实施本发明的所述模式的各种修改旨在落入所附权利要求的范围内。
序列表
<110> 益普生生物制药有限公司
<120> 弗林蛋白酶活化
<130> P67091WO
<150> GB 2104294.0
<151> 2021-03-26
<160> 78
<170> PatentIn version 3.5
<210> 1
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 弗林蛋白酶切割共有序列
<220>
<221> misc_feature
<222> (2)..(3)
<223> Xaa可以是任何天然产生的氨基酸
<400> 1
Arg Xaa Xaa Arg
1
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<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 弗林蛋白酶切割位点共有序列
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<221> misc_feature
<222> (2)..(2)
<223> Xaa可以是任何天然产生的氨基酸
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Arg Xaa Lys Arg
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<210> 3
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 弗林蛋白酶切割位点共有序列
<220>
<221> misc_feature
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<223> Xaa可以是任何天然产生的氨基酸
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Arg Xaa Arg Arg
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Arg Lys Lys Arg
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Lys Gln Lys Ser Ser Asn Ser Arg Lys Lys Arg
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Ser Arg Lys Lys Arg Ser
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Ser Arg Lys Arg Arg Ser
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Ser Lys Arg Lys Lys Arg Ser
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Cys Val Arg Gly Ile Ile Thr Ser Lys Thr Lys Ser Leu Ser Arg Lys
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Cys Val Arg Gly Ile Ile Thr Ser Lys Thr Lys Ser Ser Lys Arg Lys
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Cys Val Arg Gly Ile Thr Ser Ser Lys Ser Arg Arg Arg Lys Lys Arg
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Cys Val Arg Gly Ile Ala Gly Leu Ile Thr Gly Gly Arg Arg Thr Arg
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Cys Val Arg Gly Ile Ile Lys Val Ala Asp Ser Leu Ser Thr Arg Lys
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Gln Lys Arg Ala Leu Asn Asp Leu Cys
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<213> 人工序列
<220>
<223> 基于具有弗林蛋白酶切割位点的BoNT/A1活化环的外源性活化环
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Cys Val Arg Gly Ile Leu Ala Thr Gly Leu Arg Asn Thr Ser Gln Arg
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Ser Arg Arg Arg Lys Lys Arg Gly Leu Ala Leu Asn Asp Leu Cys
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<211> 25
<212> PRT
<213> 人工序列
<220>
<223> 基于具有弗林蛋白酶切割位点的BoNT/A1活化环的外源性活化环
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Cys Val Arg Gly Ile Lys Gln Lys Ser Ser Asn Ser Arg Lys Lys Arg
1 5 10 15
Ser Thr Ser Ala Leu Asn Asp Leu Cys
20 25
<210> 23
<211> 3888
<212> DNA
<213> 人工序列
<220>
<223> 具有弗林蛋白酶切割位点的BoNT/A1的核酸序列
<400> 23
atgccgtttg tgaacaaaca gttcaactat aaagatccgg tgaacggtgt tgatatcgcc 60
tatatcaaaa ttccgaatgc aggtcagatg cagccggtta aagcctttaa aatccataac 120
aaaatttggg tgattccgga acgtgatacc tttaccaatc cggaagaagg tgatctgaat 180
ccgcctccgg aagcaaaaca ggttccggtt agctattatg atagcaccta tctgagcacc 240
gataacgaga aagataacta tctgaaaggt gtgaccaaac tgtttgaacg catttatagt 300
accgatctgg gtcgtatgct gctgaccagc attgttcgtg gtattccgtt ttggggtggt 360
agcaccattg ataccgaact gaaagttatt gacaccaact gcattaatgt gattcagccg 420
gatggtagct atcgtagcga agaactgaat ctggttatta ttggtccgag cgcagatatc 480
attcagtttg aatgtaaatc ctttggccac gaagttctga atctgacccg taatggttat 540
ggtagtaccc agtatattcg tttcagtccg gattttacct ttggctttga agaaagcctg 600
gaagttgata caaatccgct gttaggtgca ggtaaatttg caaccgatcc ggcagttacc 660
ctggcacatg aactgattca tgccggtcat cgtctgtatg gtattgcaat taatccgaac 720
cgtgtgttca aagtgaatac caacgcatat tatgaaatga gcggtctgga agtgtcattt 780
gaagaactgc gtacctttgg tggtcatgat gccaaattta tcgatagcct gcaagaaaat 840
gaatttcgcc tgtactacta taacaaattc aaggatattg cgagcaccct gaataaagcc 900
aaaagcattg ttggcaccac cgcaagcctg cagtatatga aaaatgtgtt taaagaaaaa 960
tatctgctga gcgaagatac cagcggtaaa tttagcgttg acaaactgaa attcgataaa 1020
ctgtacaaga tgctgaccga gatttatacc gaagataact tcgtgaagtt tttcaaagtg 1080
ctgaaccgca aaacctacct gaactttgat aaagccgtgt tcaaaatcaa catcgtgccg 1140
aaagtgaact ataccatcta tgatggtttt aacctgcgca ataccaatct ggcagcaaac 1200
tttaatggtc agaacaccga aatcaacaac atgaacttta ccaaactgaa gaacttcacc 1260
ggtctgttcg aattttacaa actgctgtgt gttcgtggca ttaaacaaaa atcttcgaac 1320
tcaagaaaaa agcgaagtac aagtgccctg aatgacctgt gcattaaagt gaataattgg 1380
gacctgtttt ttagcccgag cgaagataac tttaccaacg atctgaataa aggcgaagaa 1440
attaccagcg ataccaatat tgaagcagcc gaagaaaaca ttagcctgga tctgattcag 1500
cagtattatc tgaccttcaa ctttgataac gagccggaaa atatcagcat tgaaaatctg 1560
agcagcgata ttattggtca gctggaactg atgccgaata ttgaacgttt tccgaacggc 1620
aaaaaatacg agctggataa atacaccatg ttccattatc tgcgtgccca agaatttgaa 1680
catggtaaaa gccgtattgc cctgaccaat tcagttaatg aagcactgct gaacccgagc 1740
cgtgtttata ccttttttag cagcgattac gtgaaaaagg tgaacaaagc aaccgaagca 1800
gcaatgtttt taggttgggt tgaacagctg gtgtatgatt tcaccgatga aaccagcgaa 1860
gttagcacca ccgataaaat tgcagatatc accattatca tcccgtatat tggtccggca 1920
ctgaatattg gcaatatgct gtataaagat gatttcgtgg gtgccctgat ttttagcggt 1980
gcagttattc tgctggaatt tattccggaa attgccattc cggttctggg cacctttgca 2040
ctggttagct atattgcaaa taaagttctg accgtgcaga ccattgataa tgcactgagc 2100
aaacgtaacg agaaatggga tgaagtgtac aaatatatcg tgaccaattg gctggccaaa 2160
gttaataccc agattgatct gatccgcaaa aaaatgaaag aagccctgga aaatcaggca 2220
gaagcaacca aagccattat caactatcag tataaccagt acaccgaaga agagaaaaac 2280
aacatcaact tcaacatcga tgacctgagc agcaaactga atgaaagcat caataaggcc 2340
atgattaaca tcaacaaatt tctgaatcag tgcagcgtga gctatctgat gaatagcatg 2400
attccgtatg gtgtgaaacg cctggaagat tttgatgcaa gcctgaaaga tgcgctgctg 2460
aaatatatct atgataatcg tggcaccctg attggccagg ttgatcgtct gaaagataaa 2520
gttaacaata ccctgagtac cgacattccg tttcagctga gcaaatatgt tgataatcag 2580
cgtctgctga gcacctttac cgaatatatc aagaacatca tcaacaccag cattctgaat 2640
ctgcgctatg aaagcaatca tctgatcgat ctgagccgtt atgcaagcaa aatcaacatt 2700
ggtagcaaag tgaacttcga cccgattgat aaaaaccaga ttcagctgtt taatctggaa 2760
agcagcaaaa tcgaagtgat cctgaaaaac gccattgtgt ataacagcat gtatgagaat 2820
ttctcgacca gcttttggat tcgcattccg aaatacttta atagcatcag cctgaacaac 2880
gagtacacca ttattaactg catggaaaac aatagcggtt ggaaagtgag cctgaattat 2940
ggtgaaatta tctggaccct gcaggatacc caagaaatca aacagcgtgt tgtgttcaaa 3000
tacagccaga tgattaatat cagcgactat atcaaccgct ggatctttgt taccattacc 3060
aataatcgcc tgaataacag caagatctat attaacggtc gcctgattga tcagaaaccg 3120
attagcaatc tgggcaatat tcatgcgagc aacaacatta tgtttaaact ggatggttgc 3180
cgtgataccc atcgttatat ttggatcaaa tacttcaacc tgtttgataa agaactgaac 3240
gaaaaagaaa ttaaagacct gtacgacaac cagagcaatt ccggtattct gaaagacttt 3300
tggggagatt atctgcagta tgacaaaccg tattatatgc tgaacctgta tgacccgaac 3360
aaatatgtgg atgtgaacaa tgttggtatc cgtggctata tgtatctgaa aggtccgcgt 3420
ggtagcgtta tgaccaccaa catttatctg aatagcagcc tgtatcgcgg tacgaaattt 3480
atcattaaaa agtatgccag cggcaacaag gataatattg tgcgtaataa tgatcgcgtg 3540
tacattaacg ttgtggtgaa gaataaagaa tatcgcctgg caaccaatgc aagccaggca 3600
ggcgttgaaa aaattctgag cgcactggaa attccggatg ttggtaatct gagccaggtt 3660
gttgttatga aaagcaaaaa tgatcagggc atcaccaaca agtgcaaaat gaatctgcag 3720
gacaataacg gcaacgatat tggttttatt ggcttccacc agttcaacaa tattgcgaaa 3780
ctggttgcaa gcaattggta taatcgtcag attgaacgta gcagtcgtac cctgggttgt 3840
agctgggaat ttatccctgt ggatgatggt tggggtgaac gtccgctg 3888
<210> 24
<211> 1296
<212> PRT
<213> 人工序列
<220>
<223> 具有弗林蛋白酶切割位点的BoNT/A1的氨基酸序列
<400> 24
Met Pro Phe Val Asn Lys Gln Phe Asn Tyr Lys Asp Pro Val Asn Gly
1 5 10 15
Val Asp Ile Ala Tyr Ile Lys Ile Pro Asn Ala Gly Gln Met Gln Pro
20 25 30
Val Lys Ala Phe Lys Ile His Asn Lys Ile Trp Val Ile Pro Glu Arg
35 40 45
Asp Thr Phe Thr Asn Pro Glu Glu Gly Asp Leu Asn Pro Pro Pro Glu
50 55 60
Ala Lys Gln Val Pro Val Ser Tyr Tyr Asp Ser Thr Tyr Leu Ser Thr
65 70 75 80
Asp Asn Glu Lys Asp Asn Tyr Leu Lys Gly Val Thr Lys Leu Phe Glu
85 90 95
Arg Ile Tyr Ser Thr Asp Leu Gly Arg Met Leu Leu Thr Ser Ile Val
100 105 110
Arg Gly Ile Pro Phe Trp Gly Gly Ser Thr Ile Asp Thr Glu Leu Lys
115 120 125
Val Ile Asp Thr Asn Cys Ile Asn Val Ile Gln Pro Asp Gly Ser Tyr
130 135 140
Arg Ser Glu Glu Leu Asn Leu Val Ile Ile Gly Pro Ser Ala Asp Ile
145 150 155 160
Ile Gln Phe Glu Cys Lys Ser Phe Gly His Glu Val Leu Asn Leu Thr
165 170 175
Arg Asn Gly Tyr Gly Ser Thr Gln Tyr Ile Arg Phe Ser Pro Asp Phe
180 185 190
Thr Phe Gly Phe Glu Glu Ser Leu Glu Val Asp Thr Asn Pro Leu Leu
195 200 205
Gly Ala Gly Lys Phe Ala Thr Asp Pro Ala Val Thr Leu Ala His Glu
210 215 220
Leu Ile His Ala Gly His Arg Leu Tyr Gly Ile Ala Ile Asn Pro Asn
225 230 235 240
Arg Val Phe Lys Val Asn Thr Asn Ala Tyr Tyr Glu Met Ser Gly Leu
245 250 255
Glu Val Ser Phe Glu Glu Leu Arg Thr Phe Gly Gly His Asp Ala Lys
260 265 270
Phe Ile Asp Ser Leu Gln Glu Asn Glu Phe Arg Leu Tyr Tyr Tyr Asn
275 280 285
Lys Phe Lys Asp Ile Ala Ser Thr Leu Asn Lys Ala Lys Ser Ile Val
290 295 300
Gly Thr Thr Ala Ser Leu Gln Tyr Met Lys Asn Val Phe Lys Glu Lys
305 310 315 320
Tyr Leu Leu Ser Glu Asp Thr Ser Gly Lys Phe Ser Val Asp Lys Leu
325 330 335
Lys Phe Asp Lys Leu Tyr Lys Met Leu Thr Glu Ile Tyr Thr Glu Asp
340 345 350
Asn Phe Val Lys Phe Phe Lys Val Leu Asn Arg Lys Thr Tyr Leu Asn
355 360 365
Phe Asp Lys Ala Val Phe Lys Ile Asn Ile Val Pro Lys Val Asn Tyr
370 375 380
Thr Ile Tyr Asp Gly Phe Asn Leu Arg Asn Thr Asn Leu Ala Ala Asn
385 390 395 400
Phe Asn Gly Gln Asn Thr Glu Ile Asn Asn Met Asn Phe Thr Lys Leu
405 410 415
Lys Asn Phe Thr Gly Leu Phe Glu Phe Tyr Lys Leu Leu Cys Val Arg
420 425 430
Gly Ile Lys Gln Lys Ser Ser Asn Ser Arg Lys Lys Arg Ser Thr Ser
435 440 445
Ala Leu Asn Asp Leu Cys Ile Lys Val Asn Asn Trp Asp Leu Phe Phe
450 455 460
Ser Pro Ser Glu Asp Asn Phe Thr Asn Asp Leu Asn Lys Gly Glu Glu
465 470 475 480
Ile Thr Ser Asp Thr Asn Ile Glu Ala Ala Glu Glu Asn Ile Ser Leu
485 490 495
Asp Leu Ile Gln Gln Tyr Tyr Leu Thr Phe Asn Phe Asp Asn Glu Pro
500 505 510
Glu Asn Ile Ser Ile Glu Asn Leu Ser Ser Asp Ile Ile Gly Gln Leu
515 520 525
Glu Leu Met Pro Asn Ile Glu Arg Phe Pro Asn Gly Lys Lys Tyr Glu
530 535 540
Leu Asp Lys Tyr Thr Met Phe His Tyr Leu Arg Ala Gln Glu Phe Glu
545 550 555 560
His Gly Lys Ser Arg Ile Ala Leu Thr Asn Ser Val Asn Glu Ala Leu
565 570 575
Leu Asn Pro Ser Arg Val Tyr Thr Phe Phe Ser Ser Asp Tyr Val Lys
580 585 590
Lys Val Asn Lys Ala Thr Glu Ala Ala Met Phe Leu Gly Trp Val Glu
595 600 605
Gln Leu Val Tyr Asp Phe Thr Asp Glu Thr Ser Glu Val Ser Thr Thr
610 615 620
Asp Lys Ile Ala Asp Ile Thr Ile Ile Ile Pro Tyr Ile Gly Pro Ala
625 630 635 640
Leu Asn Ile Gly Asn Met Leu Tyr Lys Asp Asp Phe Val Gly Ala Leu
645 650 655
Ile Phe Ser Gly Ala Val Ile Leu Leu Glu Phe Ile Pro Glu Ile Ala
660 665 670
Ile Pro Val Leu Gly Thr Phe Ala Leu Val Ser Tyr Ile Ala Asn Lys
675 680 685
Val Leu Thr Val Gln Thr Ile Asp Asn Ala Leu Ser Lys Arg Asn Glu
690 695 700
Lys Trp Asp Glu Val Tyr Lys Tyr Ile Val Thr Asn Trp Leu Ala Lys
705 710 715 720
Val Asn Thr Gln Ile Asp Leu Ile Arg Lys Lys Met Lys Glu Ala Leu
725 730 735
Glu Asn Gln Ala Glu Ala Thr Lys Ala Ile Ile Asn Tyr Gln Tyr Asn
740 745 750
Gln Tyr Thr Glu Glu Glu Lys Asn Asn Ile Asn Phe Asn Ile Asp Asp
755 760 765
Leu Ser Ser Lys Leu Asn Glu Ser Ile Asn Lys Ala Met Ile Asn Ile
770 775 780
Asn Lys Phe Leu Asn Gln Cys Ser Val Ser Tyr Leu Met Asn Ser Met
785 790 795 800
Ile Pro Tyr Gly Val Lys Arg Leu Glu Asp Phe Asp Ala Ser Leu Lys
805 810 815
Asp Ala Leu Leu Lys Tyr Ile Tyr Asp Asn Arg Gly Thr Leu Ile Gly
820 825 830
Gln Val Asp Arg Leu Lys Asp Lys Val Asn Asn Thr Leu Ser Thr Asp
835 840 845
Ile Pro Phe Gln Leu Ser Lys Tyr Val Asp Asn Gln Arg Leu Leu Ser
850 855 860
Thr Phe Thr Glu Tyr Ile Lys Asn Ile Ile Asn Thr Ser Ile Leu Asn
865 870 875 880
Leu Arg Tyr Glu Ser Asn His Leu Ile Asp Leu Ser Arg Tyr Ala Ser
885 890 895
Lys Ile Asn Ile Gly Ser Lys Val Asn Phe Asp Pro Ile Asp Lys Asn
900 905 910
Gln Ile Gln Leu Phe Asn Leu Glu Ser Ser Lys Ile Glu Val Ile Leu
915 920 925
Lys Asn Ala Ile Val Tyr Asn Ser Met Tyr Glu Asn Phe Ser Thr Ser
930 935 940
Phe Trp Ile Arg Ile Pro Lys Tyr Phe Asn Ser Ile Ser Leu Asn Asn
945 950 955 960
Glu Tyr Thr Ile Ile Asn Cys Met Glu Asn Asn Ser Gly Trp Lys Val
965 970 975
Ser Leu Asn Tyr Gly Glu Ile Ile Trp Thr Leu Gln Asp Thr Gln Glu
980 985 990
Ile Lys Gln Arg Val Val Phe Lys Tyr Ser Gln Met Ile Asn Ile Ser
995 1000 1005
Asp Tyr Ile Asn Arg Trp Ile Phe Val Thr Ile Thr Asn Asn Arg
1010 1015 1020
Leu Asn Asn Ser Lys Ile Tyr Ile Asn Gly Arg Leu Ile Asp Gln
1025 1030 1035
Lys Pro Ile Ser Asn Leu Gly Asn Ile His Ala Ser Asn Asn Ile
1040 1045 1050
Met Phe Lys Leu Asp Gly Cys Arg Asp Thr His Arg Tyr Ile Trp
1055 1060 1065
Ile Lys Tyr Phe Asn Leu Phe Asp Lys Glu Leu Asn Glu Lys Glu
1070 1075 1080
Ile Lys Asp Leu Tyr Asp Asn Gln Ser Asn Ser Gly Ile Leu Lys
1085 1090 1095
Asp Phe Trp Gly Asp Tyr Leu Gln Tyr Asp Lys Pro Tyr Tyr Met
1100 1105 1110
Leu Asn Leu Tyr Asp Pro Asn Lys Tyr Val Asp Val Asn Asn Val
1115 1120 1125
Gly Ile Arg Gly Tyr Met Tyr Leu Lys Gly Pro Arg Gly Ser Val
1130 1135 1140
Met Thr Thr Asn Ile Tyr Leu Asn Ser Ser Leu Tyr Arg Gly Thr
1145 1150 1155
Lys Phe Ile Ile Lys Lys Tyr Ala Ser Gly Asn Lys Asp Asn Ile
1160 1165 1170
Val Arg Asn Asn Asp Arg Val Tyr Ile Asn Val Val Val Lys Asn
1175 1180 1185
Lys Glu Tyr Arg Leu Ala Thr Asn Ala Ser Gln Ala Gly Val Glu
1190 1195 1200
Lys Ile Leu Ser Ala Leu Glu Ile Pro Asp Val Gly Asn Leu Ser
1205 1210 1215
Gln Val Val Val Met Lys Ser Lys Asn Asp Gln Gly Ile Thr Asn
1220 1225 1230
Lys Cys Lys Met Asn Leu Gln Asp Asn Asn Gly Asn Asp Ile Gly
1235 1240 1245
Phe Ile Gly Phe His Gln Phe Asn Asn Ile Ala Lys Leu Val Ala
1250 1255 1260
Ser Asn Trp Tyr Asn Arg Gln Ile Glu Arg Ser Ser Arg Thr Leu
1265 1270 1275
Gly Cys Ser Trp Glu Phe Ile Pro Val Asp Asp Gly Trp Gly Glu
1280 1285 1290
Arg Pro Leu
1295
<210> 25
<211> 1296
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 25
Met Pro Phe Val Asn Lys Gln Phe Asn Tyr Lys Asp Pro Val Asn Gly
1 5 10 15
Val Asp Ile Ala Tyr Ile Lys Ile Pro Asn Val Gly Gln Met Gln Pro
20 25 30
Val Lys Ala Phe Lys Ile His Asn Lys Ile Trp Val Ile Pro Glu Arg
35 40 45
Asp Thr Phe Thr Asn Pro Glu Glu Gly Asp Leu Asn Pro Pro Pro Glu
50 55 60
Ala Lys Gln Val Pro Val Ser Tyr Tyr Asp Ser Thr Tyr Leu Ser Thr
65 70 75 80
Asp Asn Glu Lys Asp Asn Tyr Leu Lys Gly Val Thr Lys Leu Phe Glu
85 90 95
Arg Ile Tyr Ser Thr Asp Leu Gly Arg Met Leu Leu Thr Ser Ile Val
100 105 110
Arg Gly Ile Pro Phe Trp Gly Gly Ser Thr Ile Asp Thr Glu Leu Lys
115 120 125
Val Ile Asp Thr Asn Cys Ile Asn Val Ile Gln Pro Asp Gly Ser Tyr
130 135 140
Arg Ser Glu Glu Leu Asn Leu Val Ile Ile Gly Pro Ser Ala Asp Ile
145 150 155 160
Ile Gln Phe Glu Cys Lys Ser Phe Gly His Glu Val Leu Asn Leu Thr
165 170 175
Arg Asn Gly Tyr Gly Ser Thr Gln Tyr Ile Arg Phe Ser Pro Asp Phe
180 185 190
Thr Phe Gly Phe Glu Glu Ser Leu Glu Val Asp Thr Asn Pro Leu Leu
195 200 205
Gly Ala Gly Lys Phe Ala Thr Asp Pro Ala Val Thr Leu Ala His Glu
210 215 220
Leu Ile His Ala Gly His Arg Leu Tyr Gly Ile Ala Ile Asn Pro Asn
225 230 235 240
Arg Val Phe Lys Val Asn Thr Asn Ala Tyr Tyr Glu Met Ser Gly Leu
245 250 255
Glu Val Ser Phe Glu Glu Leu Arg Thr Phe Gly Gly His Asp Ala Lys
260 265 270
Phe Ile Asp Ser Leu Gln Glu Asn Glu Phe Arg Leu Tyr Tyr Tyr Asn
275 280 285
Lys Phe Lys Asp Ile Ala Ser Thr Leu Asn Lys Ala Lys Ser Ile Val
290 295 300
Gly Thr Thr Ala Ser Leu Gln Tyr Met Lys Asn Val Phe Lys Glu Lys
305 310 315 320
Tyr Leu Leu Ser Glu Asp Thr Ser Gly Lys Phe Ser Val Asp Lys Leu
325 330 335
Lys Phe Asp Lys Leu Tyr Lys Met Leu Thr Glu Ile Tyr Thr Glu Asp
340 345 350
Asn Phe Val Lys Phe Phe Lys Val Leu Asn Arg Lys Thr Tyr Leu Asn
355 360 365
Phe Asp Lys Ala Val Phe Lys Ile Asn Ile Val Pro Lys Val Asn Tyr
370 375 380
Thr Ile Tyr Asp Gly Phe Asn Leu Arg Asn Thr Asn Leu Ala Ala Asn
385 390 395 400
Phe Asn Gly Gln Asn Thr Glu Ile Asn Asn Met Asn Phe Thr Lys Leu
405 410 415
Lys Asn Phe Thr Gly Leu Phe Glu Phe Tyr Lys Leu Leu Cys Val Arg
420 425 430
Gly Ile Ile Thr Ser Lys Thr Lys Ser Leu Asp Lys Gly Tyr Asn Lys
435 440 445
Ala Leu Asn Asp Leu Cys Ile Lys Val Asn Asn Trp Asp Leu Phe Phe
450 455 460
Ser Pro Ser Glu Asp Asn Phe Thr Asn Asp Leu Asn Lys Gly Glu Glu
465 470 475 480
Ile Thr Ser Asp Thr Asn Ile Glu Ala Ala Glu Glu Asn Ile Ser Leu
485 490 495
Asp Leu Ile Gln Gln Tyr Tyr Leu Thr Phe Asn Phe Asp Asn Glu Pro
500 505 510
Glu Asn Ile Ser Ile Glu Asn Leu Ser Ser Asp Ile Ile Gly Gln Leu
515 520 525
Glu Leu Met Pro Asn Ile Glu Arg Phe Pro Asn Gly Lys Lys Tyr Glu
530 535 540
Leu Asp Lys Tyr Thr Met Phe His Tyr Leu Arg Ala Gln Glu Phe Glu
545 550 555 560
His Gly Lys Ser Arg Ile Ala Leu Thr Asn Ser Val Asn Glu Ala Leu
565 570 575
Leu Asn Pro Ser Arg Val Tyr Thr Phe Phe Ser Ser Asp Tyr Val Lys
580 585 590
Lys Val Asn Lys Ala Thr Glu Ala Ala Met Phe Leu Gly Trp Val Glu
595 600 605
Gln Leu Val Tyr Asp Phe Thr Asp Glu Thr Ser Glu Val Ser Thr Thr
610 615 620
Asp Lys Ile Ala Asp Ile Thr Ile Ile Ile Pro Tyr Ile Gly Pro Ala
625 630 635 640
Leu Asn Ile Gly Asn Met Leu Tyr Lys Asp Asp Phe Val Gly Ala Leu
645 650 655
Ile Phe Ser Gly Ala Val Ile Leu Leu Glu Phe Ile Pro Glu Ile Ala
660 665 670
Ile Pro Val Leu Gly Thr Phe Ala Leu Val Ser Tyr Ile Ala Asn Lys
675 680 685
Val Leu Thr Val Gln Thr Ile Asp Asn Ala Leu Ser Lys Arg Asn Glu
690 695 700
Lys Trp Asp Glu Val Tyr Lys Tyr Ile Val Thr Asn Trp Leu Ala Lys
705 710 715 720
Val Asn Thr Gln Ile Asp Leu Ile Arg Lys Lys Met Lys Glu Ala Leu
725 730 735
Glu Asn Gln Ala Glu Ala Thr Lys Ala Ile Ile Asn Tyr Gln Tyr Asn
740 745 750
Gln Tyr Thr Glu Glu Glu Lys Asn Asn Ile Asn Phe Asn Ile Asp Asp
755 760 765
Leu Ser Ser Lys Leu Asn Glu Ser Ile Asn Lys Ala Met Ile Asn Ile
770 775 780
Asn Lys Phe Leu Asn Gln Cys Ser Val Ser Tyr Leu Met Asn Ser Met
785 790 795 800
Ile Pro Tyr Gly Val Lys Arg Leu Glu Asp Phe Asp Ala Ser Leu Lys
805 810 815
Asp Ala Leu Leu Lys Tyr Ile Tyr Asp Asn Arg Gly Thr Leu Ile Gly
820 825 830
Gln Val Asp Arg Leu Lys Asp Lys Val Asn Asn Thr Leu Ser Thr Asp
835 840 845
Ile Pro Phe Gln Leu Ser Lys Tyr Val Asp Asn Gln Arg Leu Leu Ser
850 855 860
Thr Phe Thr Glu Tyr Ile Lys Asn Ile Ile Asn Thr Ser Ile Leu Asn
865 870 875 880
Leu Arg Tyr Glu Ser Asn His Leu Ile Asp Leu Ser Arg Tyr Ala Ser
885 890 895
Lys Ile Asn Ile Gly Ser Lys Val Asn Phe Asp Pro Ile Asp Lys Asn
900 905 910
Gln Ile Gln Leu Phe Asn Leu Glu Ser Ser Lys Ile Glu Val Ile Leu
915 920 925
Lys Asn Ala Ile Val Tyr Asn Ser Met Tyr Glu Asn Phe Ser Thr Ser
930 935 940
Phe Trp Ile Arg Ile Pro Lys Tyr Phe Asn Ser Ile Ser Leu Asn Asn
945 950 955 960
Glu Tyr Thr Ile Ile Asn Cys Met Glu Asn Asn Ser Gly Trp Lys Val
965 970 975
Ser Leu Asn Tyr Gly Glu Ile Ile Trp Thr Leu Gln Asp Thr Gln Glu
980 985 990
Ile Lys Gln Arg Val Val Phe Lys Tyr Ser Gln Met Ile Asn Ile Ser
995 1000 1005
Asp Tyr Ile Asn Arg Trp Ile Phe Val Thr Ile Thr Asn Asn Arg
1010 1015 1020
Leu Asn Asn Ser Lys Ile Tyr Ile Asn Gly Arg Leu Ile Asp Gln
1025 1030 1035
Lys Pro Ile Ser Asn Leu Gly Asn Ile His Ala Ser Asn Asn Ile
1040 1045 1050
Met Phe Lys Leu Asp Gly Cys Arg Asp Thr His Arg Tyr Ile Trp
1055 1060 1065
Ile Lys Tyr Phe Asn Leu Phe Asp Lys Glu Leu Asn Glu Lys Glu
1070 1075 1080
Ile Lys Asp Leu Tyr Asp Asn Gln Ser Asn Ser Gly Ile Leu Lys
1085 1090 1095
Asp Phe Trp Gly Asp Tyr Leu Gln Tyr Asp Lys Pro Tyr Tyr Met
1100 1105 1110
Leu Asn Leu Tyr Asp Pro Asn Lys Tyr Val Asp Val Asn Asn Val
1115 1120 1125
Gly Ile Arg Gly Tyr Met Tyr Leu Lys Gly Pro Arg Gly Ser Val
1130 1135 1140
Met Thr Thr Asn Ile Tyr Leu Asn Ser Ser Leu Tyr Arg Gly Thr
1145 1150 1155
Lys Phe Ile Ile Lys Lys Tyr Ala Ser Gly Asn Lys Asp Asn Ile
1160 1165 1170
Val Arg Asn Asn Asp Arg Val Tyr Ile Asn Val Val Val Lys Asn
1175 1180 1185
Lys Glu Tyr Arg Leu Ala Thr Asn Ala Ser Gln Ala Gly Val Glu
1190 1195 1200
Lys Ile Leu Ser Ala Leu Glu Ile Pro Asp Val Gly Asn Leu Ser
1205 1210 1215
Gln Val Val Val Met Lys Ser Lys Asn Asp Gln Gly Ile Thr Asn
1220 1225 1230
Lys Cys Lys Met Asn Leu Gln Asp Asn Asn Gly Asn Asp Ile Gly
1235 1240 1245
Phe Ile Gly Phe His Gln Phe Asn Asn Ile Ala Lys Leu Val Ala
1250 1255 1260
Ser Asn Trp Tyr Asn Arg Gln Ile Glu Arg Ser Ser Arg Thr Leu
1265 1270 1275
Gly Cys Ser Trp Glu Phe Ile Pro Val Asp Asp Gly Trp Gly Glu
1280 1285 1290
Arg Pro Leu
1295
<210> 26
<211> 1291
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 26
Met Pro Val Thr Ile Asn Asn Phe Asn Tyr Asn Asp Pro Ile Asp Asn
1 5 10 15
Asn Asn Ile Ile Met Met Glu Pro Pro Phe Ala Arg Gly Thr Gly Arg
20 25 30
Tyr Tyr Lys Ala Phe Lys Ile Thr Asp Arg Ile Trp Ile Ile Pro Glu
35 40 45
Arg Tyr Thr Phe Gly Tyr Lys Pro Glu Asp Phe Asn Lys Ser Ser Gly
50 55 60
Ile Phe Asn Arg Asp Val Cys Glu Tyr Tyr Asp Pro Asp Tyr Leu Asn
65 70 75 80
Thr Asn Asp Lys Lys Asn Ile Phe Leu Gln Thr Met Ile Lys Leu Phe
85 90 95
Asn Arg Ile Lys Ser Lys Pro Leu Gly Glu Lys Leu Leu Glu Met Ile
100 105 110
Ile Asn Gly Ile Pro Tyr Leu Gly Asp Arg Arg Val Pro Leu Glu Glu
115 120 125
Phe Asn Thr Asn Ile Ala Ser Val Thr Val Asn Lys Leu Ile Ser Asn
130 135 140
Pro Gly Glu Val Glu Arg Lys Lys Gly Ile Phe Ala Asn Leu Ile Ile
145 150 155 160
Phe Gly Pro Gly Pro Val Leu Asn Glu Asn Glu Thr Ile Asp Ile Gly
165 170 175
Ile Gln Asn His Phe Ala Ser Arg Glu Gly Phe Gly Gly Ile Met Gln
180 185 190
Met Lys Phe Cys Pro Glu Tyr Val Ser Val Phe Asn Asn Val Gln Glu
195 200 205
Asn Lys Gly Ala Ser Ile Phe Asn Arg Arg Gly Tyr Phe Ser Asp Pro
210 215 220
Ala Leu Ile Leu Met His Glu Leu Ile His Val Leu His Gly Leu Tyr
225 230 235 240
Gly Ile Lys Val Asp Asp Leu Pro Ile Val Pro Asn Glu Lys Lys Phe
245 250 255
Phe Met Gln Ser Thr Asp Ala Ile Gln Ala Glu Glu Leu Tyr Thr Phe
260 265 270
Gly Gly Gln Asp Pro Ser Ile Ile Thr Pro Ser Thr Asp Lys Ser Ile
275 280 285
Tyr Asp Lys Val Leu Gln Asn Phe Arg Gly Ile Val Asp Arg Leu Asn
290 295 300
Lys Val Leu Val Cys Ile Ser Asp Pro Asn Ile Asn Ile Asn Ile Tyr
305 310 315 320
Lys Asn Lys Phe Lys Asp Lys Tyr Lys Phe Val Glu Asp Ser Glu Gly
325 330 335
Lys Tyr Ser Ile Asp Val Glu Ser Phe Asp Lys Leu Tyr Lys Ser Leu
340 345 350
Met Phe Gly Phe Thr Glu Thr Asn Ile Ala Glu Asn Tyr Lys Ile Lys
355 360 365
Thr Arg Ala Ser Tyr Phe Ser Asp Ser Leu Pro Pro Val Lys Ile Lys
370 375 380
Asn Leu Leu Asp Asn Glu Ile Tyr Thr Ile Glu Glu Gly Phe Asn Ile
385 390 395 400
Ser Asp Lys Asp Met Glu Lys Glu Tyr Arg Gly Gln Asn Lys Ala Ile
405 410 415
Asn Lys Gln Ala Tyr Glu Glu Ile Ser Lys Glu His Leu Ala Val Tyr
420 425 430
Lys Ile Gln Met Cys Lys Ser Val Lys Ala Pro Gly Ile Cys Ile Asp
435 440 445
Val Asp Asn Glu Asp Leu Phe Phe Ile Ala Asp Lys Asn Ser Phe Ser
450 455 460
Asp Asp Leu Ser Lys Asn Glu Arg Ile Glu Tyr Asn Thr Gln Ser Asn
465 470 475 480
Tyr Ile Glu Asn Asp Phe Pro Ile Asn Glu Leu Ile Leu Asp Thr Asp
485 490 495
Leu Ile Ser Lys Ile Glu Leu Pro Ser Glu Asn Thr Glu Ser Leu Thr
500 505 510
Asp Phe Asn Val Asp Val Pro Val Tyr Glu Lys Gln Pro Ala Ile Lys
515 520 525
Lys Ile Phe Thr Asp Glu Asn Thr Ile Phe Gln Tyr Leu Tyr Ser Gln
530 535 540
Thr Phe Pro Leu Asp Ile Arg Asp Ile Ser Leu Thr Ser Ser Phe Asp
545 550 555 560
Asp Ala Leu Leu Phe Ser Asn Lys Val Tyr Ser Phe Phe Ser Met Asp
565 570 575
Tyr Ile Lys Thr Ala Asn Lys Val Val Glu Ala Gly Leu Phe Ala Gly
580 585 590
Trp Val Lys Gln Ile Val Asn Asp Phe Val Ile Glu Ala Asn Lys Ser
595 600 605
Asn Thr Met Asp Lys Ile Ala Asp Ile Ser Leu Ile Val Pro Tyr Ile
610 615 620
Gly Leu Ala Leu Asn Val Gly Asn Glu Thr Ala Lys Gly Asn Phe Glu
625 630 635 640
Asn Ala Phe Glu Ile Ala Gly Ala Ser Ile Leu Leu Glu Phe Ile Pro
645 650 655
Glu Leu Leu Ile Pro Val Val Gly Ala Phe Leu Leu Glu Ser Tyr Ile
660 665 670
Asp Asn Lys Asn Lys Ile Ile Lys Thr Ile Asp Asn Ala Leu Thr Lys
675 680 685
Arg Asn Glu Lys Trp Ser Asp Met Tyr Gly Leu Ile Val Ala Gln Trp
690 695 700
Leu Ser Thr Val Asn Thr Gln Phe Tyr Thr Ile Lys Glu Gly Met Tyr
705 710 715 720
Lys Ala Leu Asn Tyr Gln Ala Gln Ala Leu Glu Glu Ile Ile Lys Tyr
725 730 735
Arg Tyr Asn Ile Tyr Ser Glu Lys Glu Lys Ser Asn Ile Asn Ile Asp
740 745 750
Phe Asn Asp Ile Asn Ser Lys Leu Asn Glu Gly Ile Asn Gln Ala Ile
755 760 765
Asp Asn Ile Asn Asn Phe Ile Asn Gly Cys Ser Val Ser Tyr Leu Met
770 775 780
Lys Lys Met Ile Pro Leu Ala Val Glu Lys Leu Leu Asp Phe Asp Asn
785 790 795 800
Thr Leu Lys Lys Asn Leu Leu Asn Tyr Ile Asp Glu Asn Lys Leu Tyr
805 810 815
Leu Ile Gly Ser Ala Glu Tyr Glu Lys Ser Lys Val Asn Lys Tyr Leu
820 825 830
Lys Thr Ile Met Pro Phe Asp Leu Ser Ile Tyr Thr Asn Asp Thr Ile
835 840 845
Leu Ile Glu Met Phe Asn Lys Tyr Asn Ser Glu Ile Leu Asn Asn Ile
850 855 860
Ile Leu Asn Leu Arg Tyr Lys Asp Asn Asn Leu Ile Asp Leu Ser Gly
865 870 875 880
Tyr Gly Ala Lys Val Glu Val Tyr Asp Gly Val Glu Leu Asn Asp Lys
885 890 895
Asn Gln Phe Lys Leu Thr Ser Ser Ala Asn Ser Lys Ile Arg Val Thr
900 905 910
Gln Asn Gln Asn Ile Ile Phe Asn Ser Val Phe Leu Asp Phe Ser Val
915 920 925
Ser Phe Trp Ile Arg Ile Pro Lys Tyr Lys Asn Asp Gly Ile Gln Asn
930 935 940
Tyr Ile His Asn Glu Tyr Thr Ile Ile Asn Cys Met Lys Asn Asn Ser
945 950 955 960
Gly Trp Lys Ile Ser Ile Arg Gly Asn Arg Ile Ile Trp Thr Leu Ile
965 970 975
Asp Ile Asn Gly Lys Thr Lys Ser Val Phe Phe Glu Tyr Asn Ile Arg
980 985 990
Glu Asp Ile Ser Glu Tyr Ile Asn Arg Trp Phe Phe Val Thr Ile Thr
995 1000 1005
Asn Asn Leu Asn Asn Ala Lys Ile Tyr Ile Asn Gly Lys Leu Glu
1010 1015 1020
Ser Asn Thr Asp Ile Lys Asp Ile Arg Glu Val Ile Ala Asn Gly
1025 1030 1035
Glu Ile Ile Phe Lys Leu Asp Gly Asp Ile Asp Arg Thr Gln Phe
1040 1045 1050
Ile Trp Met Lys Tyr Phe Ser Ile Phe Asn Thr Glu Leu Ser Gln
1055 1060 1065
Ser Asn Ile Glu Glu Arg Tyr Lys Ile Gln Ser Tyr Ser Glu Tyr
1070 1075 1080
Leu Lys Asp Phe Trp Gly Asn Pro Leu Met Tyr Asn Lys Glu Tyr
1085 1090 1095
Tyr Met Phe Asn Ala Gly Asn Lys Asn Ser Tyr Ile Lys Leu Lys
1100 1105 1110
Lys Asp Ser Pro Val Gly Glu Ile Leu Thr Arg Ser Lys Tyr Asn
1115 1120 1125
Gln Asn Ser Lys Tyr Ile Asn Tyr Arg Asp Leu Tyr Ile Gly Glu
1130 1135 1140
Lys Phe Ile Ile Arg Arg Lys Ser Asn Ser Gln Ser Ile Asn Asp
1145 1150 1155
Asp Ile Val Arg Lys Glu Asp Tyr Ile Tyr Leu Asp Phe Phe Asn
1160 1165 1170
Leu Asn Gln Glu Trp Arg Val Tyr Thr Tyr Lys Tyr Phe Lys Lys
1175 1180 1185
Glu Glu Glu Lys Leu Phe Leu Ala Pro Ile Ser Asp Ser Asp Glu
1190 1195 1200
Phe Tyr Asn Thr Ile Gln Ile Lys Glu Tyr Asp Glu Gln Pro Thr
1205 1210 1215
Tyr Ser Cys Gln Leu Leu Phe Lys Lys Asp Glu Glu Ser Thr Asp
1220 1225 1230
Glu Ile Gly Leu Ile Gly Ile His Arg Phe Tyr Glu Ser Gly Ile
1235 1240 1245
Val Phe Glu Glu Tyr Lys Asp Tyr Phe Cys Ile Ser Lys Trp Tyr
1250 1255 1260
Leu Lys Glu Val Lys Arg Lys Pro Tyr Asn Leu Lys Leu Gly Cys
1265 1270 1275
Asn Trp Gln Phe Ile Pro Lys Asp Glu Gly Trp Thr Glu
1280 1285 1290
<210> 27
<211> 1291
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 27
Met Pro Ile Thr Ile Asn Asn Phe Asn Tyr Ser Asp Pro Val Asp Asn
1 5 10 15
Lys Asn Ile Leu Tyr Leu Asp Thr His Leu Asn Thr Leu Ala Asn Glu
20 25 30
Pro Glu Lys Ala Phe Arg Ile Thr Gly Asn Ile Trp Val Ile Pro Asp
35 40 45
Arg Phe Ser Arg Asn Ser Asn Pro Asn Leu Asn Lys Pro Pro Arg Val
50 55 60
Thr Ser Pro Lys Ser Gly Tyr Tyr Asp Pro Asn Tyr Leu Ser Thr Asp
65 70 75 80
Ser Asp Lys Asp Pro Phe Leu Lys Glu Ile Ile Lys Leu Phe Lys Arg
85 90 95
Ile Asn Ser Arg Glu Ile Gly Glu Glu Leu Ile Tyr Arg Leu Ser Thr
100 105 110
Asp Ile Pro Phe Pro Gly Asn Asn Asn Thr Pro Ile Asn Thr Phe Asp
115 120 125
Phe Asp Val Asp Phe Asn Ser Val Asp Val Lys Thr Arg Gln Gly Asn
130 135 140
Asn Trp Val Lys Thr Gly Ser Ile Asn Pro Ser Val Ile Ile Thr Gly
145 150 155 160
Pro Arg Glu Asn Ile Ile Asp Pro Glu Thr Ser Thr Phe Lys Leu Thr
165 170 175
Asn Asn Thr Phe Ala Ala Gln Glu Gly Phe Gly Ala Leu Ser Ile Ile
180 185 190
Ser Ile Ser Pro Arg Phe Met Leu Thr Tyr Ser Asn Ala Thr Asn Asp
195 200 205
Val Gly Glu Gly Arg Phe Ser Lys Ser Glu Phe Cys Met Asp Pro Ile
210 215 220
Leu Ile Leu Met His Glu Leu Asn His Ala Met His Asn Leu Tyr Gly
225 230 235 240
Ile Ala Ile Pro Asn Asp Gln Thr Ile Ser Ser Val Thr Ser Asn Ile
245 250 255
Phe Tyr Ser Gln Tyr Asn Val Lys Leu Glu Tyr Ala Glu Ile Tyr Ala
260 265 270
Phe Gly Gly Pro Thr Ile Asp Leu Ile Pro Lys Ser Ala Arg Lys Tyr
275 280 285
Phe Glu Glu Lys Ala Leu Asp Tyr Tyr Arg Ser Ile Ala Lys Arg Leu
290 295 300
Asn Ser Ile Thr Thr Ala Asn Pro Ser Ser Phe Asn Lys Tyr Ile Gly
305 310 315 320
Glu Tyr Lys Gln Lys Leu Ile Arg Lys Tyr Arg Phe Val Val Glu Ser
325 330 335
Ser Gly Glu Val Thr Val Asn Arg Asn Lys Phe Val Glu Leu Tyr Asn
340 345 350
Glu Leu Thr Gln Ile Phe Thr Glu Phe Asn Tyr Ala Lys Ile Tyr Asn
355 360 365
Val Gln Asn Arg Lys Ile Tyr Leu Ser Asn Val Tyr Thr Pro Val Thr
370 375 380
Ala Asn Ile Leu Asp Asp Asn Val Tyr Asp Ile Gln Asn Gly Phe Asn
385 390 395 400
Ile Pro Lys Ser Asn Leu Asn Val Leu Phe Met Gly Gln Asn Leu Ser
405 410 415
Arg Asn Pro Ala Leu Arg Lys Val Asn Pro Glu Asn Met Leu Tyr Leu
420 425 430
Phe Thr Lys Phe Cys His Lys Ala Ile Asp Gly Arg Ser Leu Tyr Asn
435 440 445
Lys Thr Leu Asp Cys Arg Glu Leu Leu Val Lys Asn Thr Asp Leu Pro
450 455 460
Phe Ile Gly Asp Ile Ser Asp Val Lys Thr Asp Ile Phe Leu Arg Lys
465 470 475 480
Asp Ile Asn Glu Glu Thr Glu Val Ile Tyr Tyr Pro Asp Asn Val Ser
485 490 495
Val Asp Gln Val Ile Leu Ser Lys Asn Thr Ser Glu His Gly Gln Leu
500 505 510
Asp Leu Leu Tyr Pro Ser Ile Asp Ser Glu Ser Glu Ile Leu Pro Gly
515 520 525
Glu Asn Gln Val Phe Tyr Asp Asn Arg Thr Gln Asn Val Asp Tyr Leu
530 535 540
Asn Ser Tyr Tyr Tyr Leu Glu Ser Gln Lys Leu Ser Asp Asn Val Glu
545 550 555 560
Asp Phe Thr Phe Thr Arg Ser Ile Glu Glu Ala Leu Asp Asn Ser Ala
565 570 575
Lys Val Tyr Thr Tyr Phe Pro Thr Leu Ala Asn Lys Val Asn Ala Gly
580 585 590
Val Gln Gly Gly Leu Phe Leu Met Trp Ala Asn Asp Val Val Glu Asp
595 600 605
Phe Thr Thr Asn Ile Leu Arg Lys Asp Thr Leu Asp Lys Ile Ser Asp
610 615 620
Val Ser Ala Ile Ile Pro Tyr Ile Gly Pro Ala Leu Asn Ile Ser Asn
625 630 635 640
Ser Val Arg Arg Gly Asn Phe Thr Glu Ala Phe Ala Val Thr Gly Val
645 650 655
Thr Ile Leu Leu Glu Ala Phe Pro Glu Phe Thr Ile Pro Ala Leu Gly
660 665 670
Ala Phe Val Ile Tyr Ser Lys Val Gln Glu Arg Asn Glu Ile Ile Lys
675 680 685
Thr Ile Asp Asn Cys Leu Glu Gln Arg Ile Lys Arg Trp Lys Asp Ser
690 695 700
Tyr Glu Trp Met Met Gly Thr Trp Leu Ser Arg Ile Ile Thr Gln Phe
705 710 715 720
Asn Asn Ile Ser Tyr Gln Met Tyr Asp Ser Leu Asn Tyr Gln Ala Gly
725 730 735
Ala Ile Lys Ala Lys Ile Asp Leu Glu Tyr Lys Lys Tyr Ser Gly Ser
740 745 750
Asp Lys Glu Asn Ile Lys Ser Gln Val Glu Asn Leu Lys Asn Ser Leu
755 760 765
Asp Val Lys Ile Ser Glu Ala Met Asn Asn Ile Asn Lys Phe Ile Arg
770 775 780
Glu Cys Ser Val Thr Tyr Leu Phe Lys Asn Met Leu Pro Lys Val Ile
785 790 795 800
Asp Glu Leu Asn Glu Phe Asp Arg Asn Thr Lys Ala Lys Leu Ile Asn
805 810 815
Leu Ile Asp Ser His Asn Ile Ile Leu Val Gly Glu Val Asp Lys Leu
820 825 830
Lys Ala Lys Val Asn Asn Ser Phe Gln Asn Thr Ile Pro Phe Asn Ile
835 840 845
Phe Ser Tyr Thr Asn Asn Ser Leu Leu Lys Asp Ile Ile Asn Glu Tyr
850 855 860
Phe Asn Asn Ile Asn Asp Ser Lys Ile Leu Ser Leu Gln Asn Arg Lys
865 870 875 880
Asn Thr Leu Val Asp Thr Ser Gly Tyr Asn Ala Glu Val Ser Glu Glu
885 890 895
Gly Asp Val Gln Leu Asn Pro Ile Phe Pro Phe Asp Phe Lys Leu Gly
900 905 910
Ser Ser Gly Glu Asp Arg Gly Lys Val Ile Val Thr Gln Asn Glu Asn
915 920 925
Ile Val Tyr Asn Ser Met Tyr Glu Ser Phe Ser Ile Ser Phe Trp Ile
930 935 940
Arg Ile Asn Lys Trp Val Ser Asn Leu Pro Gly Tyr Thr Ile Ile Asp
945 950 955 960
Ser Val Lys Asn Asn Ser Gly Trp Ser Ile Gly Ile Ile Ser Asn Phe
965 970 975
Leu Val Phe Thr Leu Lys Gln Asn Glu Asp Ser Glu Gln Ser Ile Asn
980 985 990
Phe Ser Tyr Asp Ile Ser Asn Asn Ala Pro Gly Tyr Asn Lys Trp Phe
995 1000 1005
Phe Val Thr Val Thr Asn Asn Met Met Gly Asn Met Lys Ile Tyr
1010 1015 1020
Ile Asn Gly Lys Leu Ile Asp Thr Ile Lys Val Lys Glu Leu Thr
1025 1030 1035
Gly Ile Asn Phe Ser Lys Thr Ile Thr Phe Glu Ile Asn Lys Ile
1040 1045 1050
Pro Asp Thr Gly Leu Ile Thr Ser Asp Ser Asp Asn Ile Asn Met
1055 1060 1065
Trp Ile Arg Asp Phe Tyr Ile Phe Ala Lys Glu Leu Asp Gly Lys
1070 1075 1080
Asp Ile Asn Ile Leu Phe Asn Ser Leu Gln Tyr Thr Asn Val Val
1085 1090 1095
Lys Asp Tyr Trp Gly Asn Asp Leu Arg Tyr Asn Lys Glu Tyr Tyr
1100 1105 1110
Met Val Asn Ile Asp Tyr Leu Asn Arg Tyr Met Tyr Ala Asn Ser
1115 1120 1125
Arg Gln Ile Val Phe Asn Thr Arg Arg Asn Asn Asn Asp Phe Asn
1130 1135 1140
Glu Gly Tyr Lys Ile Ile Ile Lys Arg Ile Arg Gly Asn Thr Asn
1145 1150 1155
Asp Thr Arg Val Arg Gly Gly Asp Ile Leu Tyr Phe Asp Met Thr
1160 1165 1170
Ile Asn Asn Lys Ala Tyr Asn Leu Phe Met Lys Asn Glu Thr Met
1175 1180 1185
Tyr Ala Asp Asn His Ser Thr Glu Asp Ile Tyr Ala Ile Gly Leu
1190 1195 1200
Arg Glu Gln Thr Lys Asp Ile Asn Asp Asn Ile Ile Phe Gln Ile
1205 1210 1215
Gln Pro Met Asn Asn Thr Tyr Tyr Tyr Ala Ser Gln Ile Phe Lys
1220 1225 1230
Ser Asn Phe Asn Gly Glu Asn Ile Ser Gly Ile Cys Ser Ile Gly
1235 1240 1245
Thr Tyr Arg Phe Arg Leu Gly Gly Asp Trp Tyr Arg His Asn Tyr
1250 1255 1260
Leu Val Pro Thr Val Lys Gln Gly Asn Tyr Ala Ser Leu Leu Glu
1265 1270 1275
Ser Thr Ser Thr His Trp Gly Phe Val Pro Val Ser Glu
1280 1285 1290
<210> 28
<211> 1276
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 28
Met Thr Trp Pro Val Lys Asp Phe Asn Tyr Ser Asp Pro Val Asn Asp
1 5 10 15
Asn Asp Ile Leu Tyr Leu Arg Ile Pro Gln Asn Lys Leu Ile Thr Thr
20 25 30
Pro Val Lys Ala Phe Met Ile Thr Gln Asn Ile Trp Val Ile Pro Glu
35 40 45
Arg Phe Ser Ser Asp Thr Asn Pro Ser Leu Ser Lys Pro Pro Arg Pro
50 55 60
Thr Ser Lys Tyr Gln Ser Tyr Tyr Asp Pro Ser Tyr Leu Ser Thr Asp
65 70 75 80
Glu Gln Lys Asp Thr Phe Leu Lys Gly Ile Ile Lys Leu Phe Lys Arg
85 90 95
Ile Asn Glu Arg Asp Ile Gly Lys Lys Leu Ile Asn Tyr Leu Val Val
100 105 110
Gly Ser Pro Phe Met Gly Asp Ser Ser Thr Pro Glu Asp Thr Phe Asp
115 120 125
Phe Thr Arg His Thr Thr Asn Ile Ala Val Glu Lys Phe Glu Asn Gly
130 135 140
Ser Trp Lys Val Thr Asn Ile Ile Thr Pro Ser Val Leu Ile Phe Gly
145 150 155 160
Pro Leu Pro Asn Ile Leu Asp Tyr Thr Ala Ser Leu Thr Leu Gln Gly
165 170 175
Gln Gln Ser Asn Pro Ser Phe Glu Gly Phe Gly Thr Leu Ser Ile Leu
180 185 190
Lys Val Ala Pro Glu Phe Leu Leu Thr Phe Ser Asp Val Thr Ser Asn
195 200 205
Gln Ser Ser Ala Val Leu Gly Lys Ser Ile Phe Cys Met Asp Pro Val
210 215 220
Ile Ala Leu Met His Glu Leu Thr His Ser Leu His Gln Leu Tyr Gly
225 230 235 240
Ile Asn Ile Pro Ser Asp Lys Arg Ile Arg Pro Gln Val Ser Glu Gly
245 250 255
Phe Phe Ser Gln Asp Gly Pro Asn Val Gln Phe Glu Glu Leu Tyr Thr
260 265 270
Phe Gly Gly Leu Asp Val Glu Ile Ile Pro Gln Ile Glu Arg Ser Gln
275 280 285
Leu Arg Glu Lys Ala Leu Gly His Tyr Lys Asp Ile Ala Lys Arg Leu
290 295 300
Asn Asn Ile Asn Lys Thr Ile Pro Ser Ser Trp Ile Ser Asn Ile Asp
305 310 315 320
Lys Tyr Lys Lys Ile Phe Ser Glu Lys Tyr Asn Phe Asp Lys Asp Asn
325 330 335
Thr Gly Asn Phe Val Val Asn Ile Asp Lys Phe Asn Ser Leu Tyr Ser
340 345 350
Asp Leu Thr Asn Val Met Ser Glu Val Val Tyr Ser Ser Gln Tyr Asn
355 360 365
Val Lys Asn Arg Thr His Tyr Phe Ser Arg His Tyr Leu Pro Val Phe
370 375 380
Ala Asn Ile Leu Asp Asp Asn Ile Tyr Thr Ile Arg Asp Gly Phe Asn
385 390 395 400
Leu Thr Asn Lys Gly Phe Asn Ile Glu Asn Ser Gly Gln Asn Ile Glu
405 410 415
Arg Asn Pro Ala Leu Gln Lys Leu Ser Ser Glu Ser Val Val Asp Leu
420 425 430
Phe Thr Lys Val Cys Leu Arg Leu Thr Lys Asn Ser Arg Asp Asp Ser
435 440 445
Thr Cys Ile Lys Val Lys Asn Asn Arg Leu Pro Tyr Val Ala Asp Lys
450 455 460
Asp Ser Ile Ser Gln Glu Ile Phe Glu Asn Lys Ile Ile Thr Asp Glu
465 470 475 480
Thr Asn Val Gln Asn Tyr Ser Asp Lys Phe Ser Leu Asp Glu Ser Ile
485 490 495
Leu Asp Gly Gln Val Pro Ile Asn Pro Glu Ile Val Asp Pro Leu Leu
500 505 510
Pro Asn Val Asn Met Glu Pro Leu Asn Leu Pro Gly Glu Glu Ile Val
515 520 525
Phe Tyr Asp Asp Ile Thr Lys Tyr Val Asp Tyr Leu Asn Ser Tyr Tyr
530 535 540
Tyr Leu Glu Ser Gln Lys Leu Ser Asn Asn Val Glu Asn Ile Thr Leu
545 550 555 560
Thr Thr Ser Val Glu Glu Ala Leu Gly Tyr Ser Asn Lys Ile Tyr Thr
565 570 575
Phe Leu Pro Ser Leu Ala Glu Lys Val Asn Lys Gly Val Gln Ala Gly
580 585 590
Leu Phe Leu Asn Trp Ala Asn Glu Val Val Glu Asp Phe Thr Thr Asn
595 600 605
Ile Met Lys Lys Asp Thr Leu Asp Lys Ile Ser Asp Val Ser Val Ile
610 615 620
Ile Pro Tyr Ile Gly Pro Ala Leu Asn Ile Gly Asn Ser Ala Leu Arg
625 630 635 640
Gly Asn Phe Asn Gln Ala Phe Ala Thr Ala Gly Val Ala Phe Leu Leu
645 650 655
Glu Gly Phe Pro Glu Phe Thr Ile Pro Ala Leu Gly Val Phe Thr Phe
660 665 670
Tyr Ser Ser Ile Gln Glu Arg Glu Lys Ile Ile Lys Thr Ile Glu Asn
675 680 685
Cys Leu Glu Gln Arg Val Lys Arg Trp Lys Asp Ser Tyr Gln Trp Met
690 695 700
Val Ser Asn Trp Leu Ser Arg Ile Thr Thr Gln Phe Asn His Ile Asn
705 710 715 720
Tyr Gln Met Tyr Asp Ser Leu Ser Tyr Gln Ala Asp Ala Ile Lys Ala
725 730 735
Lys Ile Asp Leu Glu Tyr Lys Lys Tyr Ser Gly Ser Asp Lys Glu Asn
740 745 750
Ile Lys Ser Gln Val Glu Asn Leu Lys Asn Ser Leu Asp Val Lys Ile
755 760 765
Ser Glu Ala Met Asn Asn Ile Asn Lys Phe Ile Arg Glu Cys Ser Val
770 775 780
Thr Tyr Leu Phe Lys Asn Met Leu Pro Lys Val Ile Asp Glu Leu Asn
785 790 795 800
Lys Phe Asp Leu Arg Thr Lys Thr Glu Leu Ile Asn Leu Ile Asp Ser
805 810 815
His Asn Ile Ile Leu Val Gly Glu Val Asp Arg Leu Lys Ala Lys Val
820 825 830
Asn Glu Ser Phe Glu Asn Thr Met Pro Phe Asn Ile Phe Ser Tyr Thr
835 840 845
Asn Asn Ser Leu Leu Lys Asp Ile Ile Asn Glu Tyr Phe Asn Ser Ile
850 855 860
Asn Asp Ser Lys Ile Leu Ser Leu Gln Asn Lys Lys Asn Ala Leu Val
865 870 875 880
Asp Thr Ser Gly Tyr Asn Ala Glu Val Arg Val Gly Asp Asn Val Gln
885 890 895
Leu Asn Thr Ile Tyr Thr Asn Asp Phe Lys Leu Ser Ser Ser Gly Asp
900 905 910
Lys Ile Ile Val Asn Leu Asn Asn Asn Ile Leu Tyr Ser Ala Ile Tyr
915 920 925
Glu Asn Ser Ser Val Ser Phe Trp Ile Lys Ile Ser Lys Asp Leu Thr
930 935 940
Asn Ser His Asn Glu Tyr Thr Ile Ile Asn Ser Ile Glu Gln Asn Ser
945 950 955 960
Gly Trp Lys Leu Cys Ile Arg Asn Gly Asn Ile Glu Trp Ile Leu Gln
965 970 975
Asp Val Asn Arg Lys Tyr Lys Ser Leu Ile Phe Asp Tyr Ser Glu Ser
980 985 990
Leu Ser His Thr Gly Tyr Thr Asn Lys Trp Phe Phe Val Thr Ile Thr
995 1000 1005
Asn Asn Ile Met Gly Tyr Met Lys Leu Tyr Ile Asn Gly Glu Leu
1010 1015 1020
Lys Gln Ser Gln Lys Ile Glu Asp Leu Asp Glu Val Lys Leu Asp
1025 1030 1035
Lys Thr Ile Val Phe Gly Ile Asp Glu Asn Ile Asp Glu Asn Gln
1040 1045 1050
Met Leu Trp Ile Arg Asp Phe Asn Ile Phe Ser Lys Glu Leu Ser
1055 1060 1065
Asn Glu Asp Ile Asn Ile Val Tyr Glu Gly Gln Ile Leu Arg Asn
1070 1075 1080
Val Ile Lys Asp Tyr Trp Gly Asn Pro Leu Lys Phe Asp Thr Glu
1085 1090 1095
Tyr Tyr Ile Ile Asn Asp Asn Tyr Ile Asp Arg Tyr Ile Ala Pro
1100 1105 1110
Glu Ser Asn Val Leu Val Leu Val Gln Tyr Pro Asp Arg Ser Lys
1115 1120 1125
Leu Tyr Thr Gly Asn Pro Ile Thr Ile Lys Ser Val Ser Asp Lys
1130 1135 1140
Asn Pro Tyr Ser Arg Ile Leu Asn Gly Asp Asn Ile Ile Leu His
1145 1150 1155
Met Leu Tyr Asn Ser Arg Lys Tyr Met Ile Ile Arg Asp Thr Asp
1160 1165 1170
Thr Ile Tyr Ala Thr Gln Gly Gly Glu Cys Ser Gln Asn Cys Val
1175 1180 1185
Tyr Ala Leu Lys Leu Gln Ser Asn Leu Gly Asn Tyr Gly Ile Gly
1190 1195 1200
Ile Phe Ser Ile Lys Asn Ile Val Ser Lys Asn Lys Tyr Cys Ser
1205 1210 1215
Gln Ile Phe Ser Ser Phe Arg Glu Asn Thr Met Leu Leu Ala Asp
1220 1225 1230
Ile Tyr Lys Pro Trp Arg Phe Ser Phe Lys Asn Ala Tyr Thr Pro
1235 1240 1245
Val Ala Val Thr Asn Tyr Glu Thr Lys Leu Leu Ser Thr Ser Ser
1250 1255 1260
Phe Trp Lys Phe Ile Ser Arg Asp Pro Gly Trp Val Glu
1265 1270 1275
<210> 29
<211> 1251
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 29
Met Pro Lys Ile Asn Ser Phe Asn Tyr Asn Asp Pro Val Asn Asp Arg
1 5 10 15
Thr Ile Leu Tyr Ile Lys Pro Gly Gly Cys Gln Glu Phe Tyr Lys Ser
20 25 30
Phe Asn Ile Met Lys Asn Ile Trp Ile Ile Pro Glu Arg Asn Val Ile
35 40 45
Gly Thr Thr Pro Gln Asp Phe His Pro Pro Thr Ser Leu Lys Asn Gly
50 55 60
Asp Ser Ser Tyr Tyr Asp Pro Asn Tyr Leu Gln Ser Asp Glu Glu Lys
65 70 75 80
Asp Arg Phe Leu Lys Ile Val Thr Lys Ile Phe Asn Arg Ile Asn Asn
85 90 95
Asn Leu Ser Gly Gly Ile Leu Leu Glu Glu Leu Ser Lys Ala Asn Pro
100 105 110
Tyr Leu Gly Asn Asp Asn Thr Pro Asp Asn Gln Phe His Ile Gly Asp
115 120 125
Ala Ser Ala Val Glu Ile Lys Phe Ser Asn Gly Ser Gln Asp Ile Leu
130 135 140
Leu Pro Asn Val Ile Ile Met Gly Ala Glu Pro Asp Leu Phe Glu Thr
145 150 155 160
Asn Ser Ser Asn Ile Ser Leu Arg Asn Asn Tyr Met Pro Ser Asn His
165 170 175
Arg Phe Gly Ser Ile Ala Ile Val Thr Phe Ser Pro Glu Tyr Ser Phe
180 185 190
Arg Phe Asn Asp Asn Cys Met Asn Glu Phe Ile Gln Asp Pro Ala Leu
195 200 205
Thr Leu Met His Glu Leu Ile His Ser Leu His Gly Leu Tyr Gly Ala
210 215 220
Lys Gly Ile Thr Thr Lys Tyr Thr Ile Thr Gln Lys Gln Asn Pro Leu
225 230 235 240
Ile Thr Asn Ile Arg Gly Thr Asn Ile Glu Glu Phe Leu Thr Phe Gly
245 250 255
Gly Thr Asp Leu Asn Ile Ile Thr Ser Ala Gln Ser Asn Asp Ile Tyr
260 265 270
Thr Asn Leu Leu Ala Asp Tyr Lys Lys Ile Ala Ser Lys Leu Ser Lys
275 280 285
Val Gln Val Ser Asn Pro Leu Leu Asn Pro Tyr Lys Asp Val Phe Glu
290 295 300
Ala Lys Tyr Gly Leu Asp Lys Asp Ala Ser Gly Ile Tyr Ser Val Asn
305 310 315 320
Ile Asn Lys Phe Asn Asp Ile Phe Lys Lys Leu Tyr Ser Phe Thr Glu
325 330 335
Phe Asp Leu Arg Thr Lys Phe Gln Val Lys Cys Arg Gln Thr Tyr Ile
340 345 350
Gly Gln Tyr Lys Tyr Phe Lys Leu Ser Asn Leu Leu Asn Asp Ser Ile
355 360 365
Tyr Asn Ile Ser Glu Gly Tyr Asn Ile Asn Asn Leu Lys Val Asn Phe
370 375 380
Arg Gly Gln Asn Ala Asn Leu Asn Pro Arg Ile Ile Thr Pro Ile Thr
385 390 395 400
Gly Arg Gly Leu Val Lys Lys Ile Ile Arg Phe Cys Lys Asn Ile Val
405 410 415
Ser Val Lys Gly Ile Arg Lys Ser Ile Cys Ile Glu Ile Asn Asn Gly
420 425 430
Glu Leu Phe Phe Val Ala Ser Glu Asn Ser Tyr Asn Asp Asp Asn Ile
435 440 445
Asn Thr Pro Lys Glu Ile Asp Asp Thr Val Thr Ser Asn Asn Asn Tyr
450 455 460
Glu Asn Asp Leu Asp Gln Val Ile Leu Asn Phe Asn Ser Glu Ser Ala
465 470 475 480
Pro Gly Leu Ser Asp Glu Lys Leu Asn Leu Thr Ile Gln Asn Asp Ala
485 490 495
Tyr Ile Pro Lys Tyr Asp Ser Asn Gly Thr Ser Asp Ile Glu Gln His
500 505 510
Asp Val Asn Glu Leu Asn Val Phe Phe Tyr Leu Asp Ala Gln Lys Val
515 520 525
Pro Glu Gly Glu Asn Asn Val Asn Leu Thr Ser Ser Ile Asp Thr Ala
530 535 540
Leu Leu Glu Gln Pro Lys Ile Tyr Thr Phe Phe Ser Ser Glu Phe Ile
545 550 555 560
Asn Asn Val Asn Lys Pro Val Gln Ala Ala Leu Phe Val Ser Trp Ile
565 570 575
Gln Gln Val Leu Val Asp Phe Thr Thr Glu Ala Asn Gln Lys Ser Thr
580 585 590
Val Asp Lys Ile Ala Asp Ile Ser Ile Val Val Pro Tyr Ile Gly Leu
595 600 605
Ala Leu Asn Ile Gly Asn Glu Ala Gln Lys Gly Asn Phe Lys Asp Ala
610 615 620
Leu Glu Leu Leu Gly Ala Gly Ile Leu Leu Glu Phe Glu Pro Glu Leu
625 630 635 640
Leu Ile Pro Thr Ile Leu Val Phe Thr Ile Lys Ser Phe Leu Gly Ser
645 650 655
Ser Asp Asn Lys Asn Lys Val Ile Lys Ala Ile Asn Asn Ala Leu Lys
660 665 670
Glu Arg Asp Glu Lys Trp Lys Glu Val Tyr Ser Phe Ile Val Ser Asn
675 680 685
Trp Met Thr Lys Ile Asn Thr Gln Phe Asn Lys Arg Lys Glu Gln Met
690 695 700
Tyr Gln Ala Leu Gln Asn Gln Val Asn Ala Ile Lys Thr Ile Ile Glu
705 710 715 720
Ser Lys Tyr Asn Ser Tyr Thr Leu Glu Glu Lys Asn Glu Leu Thr Asn
725 730 735
Lys Tyr Asp Ile Lys Gln Ile Glu Asn Glu Leu Asn Gln Lys Val Ser
740 745 750
Ile Ala Met Asn Asn Ile Asp Arg Phe Leu Thr Glu Ser Ser Ile Ser
755 760 765
Tyr Leu Met Lys Ile Ile Asn Glu Val Lys Ile Asn Lys Leu Arg Glu
770 775 780
Tyr Asp Glu Asn Val Lys Thr Tyr Leu Leu Asn Tyr Ile Ile Gln His
785 790 795 800
Gly Ser Ile Leu Gly Glu Ser Gln Gln Glu Leu Asn Ser Met Val Thr
805 810 815
Asp Thr Leu Asn Asn Ser Ile Pro Phe Lys Leu Ser Ser Tyr Thr Asp
820 825 830
Asp Lys Ile Leu Ile Ser Tyr Phe Asn Lys Phe Phe Lys Arg Ile Lys
835 840 845
Ser Ser Ser Val Leu Asn Met Arg Tyr Lys Asn Asp Lys Tyr Val Asp
850 855 860
Thr Ser Gly Tyr Asp Ser Asn Ile Asn Ile Asn Gly Asp Val Tyr Lys
865 870 875 880
Tyr Pro Thr Asn Lys Asn Gln Phe Gly Ile Tyr Asn Asp Lys Leu Ser
885 890 895
Glu Val Asn Ile Ser Gln Asn Asp Tyr Ile Ile Tyr Asp Asn Lys Tyr
900 905 910
Lys Asn Phe Ser Ile Ser Phe Trp Val Arg Ile Pro Asn Tyr Asp Asn
915 920 925
Lys Ile Val Asn Val Asn Asn Glu Tyr Thr Ile Ile Asn Cys Met Arg
930 935 940
Asp Asn Asn Ser Gly Trp Lys Val Ser Leu Asn His Asn Glu Ile Ile
945 950 955 960
Trp Thr Phe Glu Asp Asn Arg Gly Ile Asn Gln Lys Leu Ala Phe Asn
965 970 975
Tyr Gly Asn Ala Asn Gly Ile Ser Asp Tyr Ile Asn Lys Trp Ile Phe
980 985 990
Val Thr Ile Thr Asn Asp Arg Leu Gly Asp Ser Lys Leu Tyr Ile Asn
995 1000 1005
Gly Asn Leu Ile Asp Gln Lys Ser Ile Leu Asn Leu Gly Asn Ile
1010 1015 1020
His Val Ser Asp Asn Ile Leu Phe Lys Ile Val Asn Cys Ser Tyr
1025 1030 1035
Thr Arg Tyr Ile Gly Ile Arg Tyr Phe Asn Ile Phe Asp Lys Glu
1040 1045 1050
Leu Asp Glu Thr Glu Ile Gln Thr Leu Tyr Ser Asn Glu Pro Asn
1055 1060 1065
Thr Asn Ile Leu Lys Asp Phe Trp Gly Asn Tyr Leu Leu Tyr Asp
1070 1075 1080
Lys Glu Tyr Tyr Leu Leu Asn Val Leu Lys Pro Asn Asn Phe Ile
1085 1090 1095
Asp Arg Arg Lys Asp Ser Thr Leu Ser Ile Asn Asn Ile Arg Ser
1100 1105 1110
Thr Ile Leu Leu Ala Asn Arg Leu Tyr Ser Gly Ile Lys Val Lys
1115 1120 1125
Ile Gln Arg Val Asn Asn Ser Ser Thr Asn Asp Asn Leu Val Arg
1130 1135 1140
Lys Asn Asp Gln Val Tyr Ile Asn Phe Val Ala Ser Lys Thr His
1145 1150 1155
Leu Phe Pro Leu Tyr Ala Asp Thr Ala Thr Thr Asn Lys Glu Lys
1160 1165 1170
Thr Ile Lys Ile Ser Ser Ser Gly Asn Arg Phe Asn Gln Val Val
1175 1180 1185
Val Met Asn Ser Val Gly Asn Cys Thr Met Asn Phe Lys Asn Asn
1190 1195 1200
Asn Gly Asn Asn Ile Gly Leu Leu Gly Phe Lys Ala Asp Thr Val
1205 1210 1215
Val Ala Ser Thr Trp Tyr Tyr Thr His Met Arg Asp His Thr Asn
1220 1225 1230
Ser Asn Gly Cys Phe Trp Asn Phe Ile Ser Glu Glu His Gly Trp
1235 1240 1245
Gln Glu Lys
1250
<210> 30
<211> 1278
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 30
Met Pro Val Val Ile Asn Ser Phe Asn Tyr Asn Asp Pro Val Asn Asp
1 5 10 15
Asp Thr Ile Leu Tyr Met Gln Ile Pro Tyr Glu Glu Lys Ser Lys Lys
20 25 30
Tyr Tyr Lys Ala Phe Glu Ile Met Arg Asn Val Trp Ile Ile Pro Glu
35 40 45
Arg Asn Thr Ile Gly Thr Asp Pro Ser Asp Phe Asp Pro Pro Ala Ser
50 55 60
Leu Glu Asn Gly Ser Ser Ala Tyr Tyr Asp Pro Asn Tyr Leu Thr Thr
65 70 75 80
Asp Ala Glu Lys Asp Arg Tyr Leu Lys Thr Thr Ile Lys Leu Phe Lys
85 90 95
Arg Ile Asn Ser Asn Pro Ala Gly Glu Val Leu Leu Gln Glu Ile Ser
100 105 110
Tyr Ala Lys Pro Tyr Leu Gly Asn Glu His Thr Pro Ile Asn Glu Phe
115 120 125
His Pro Val Thr Arg Thr Thr Ser Val Asn Ile Lys Ser Ser Thr Asn
130 135 140
Val Lys Ser Ser Ile Ile Leu Asn Leu Leu Val Leu Gly Ala Gly Pro
145 150 155 160
Asp Ile Phe Glu Asn Ser Ser Tyr Pro Val Arg Lys Leu Met Asp Ser
165 170 175
Gly Gly Val Tyr Asp Pro Ser Asn Asp Gly Phe Gly Ser Ile Asn Ile
180 185 190
Val Thr Phe Ser Pro Glu Tyr Glu Tyr Thr Phe Asn Asp Ile Ser Gly
195 200 205
Gly Tyr Asn Ser Ser Thr Glu Ser Phe Ile Ala Asp Pro Ala Ile Ser
210 215 220
Leu Ala His Glu Leu Ile His Ala Leu His Gly Leu Tyr Gly Ala Arg
225 230 235 240
Gly Val Thr Tyr Lys Glu Thr Ile Lys Val Lys Gln Ala Pro Leu Met
245 250 255
Ile Ala Glu Lys Pro Ile Arg Leu Glu Glu Phe Leu Thr Phe Gly Gly
260 265 270
Gln Asp Leu Asn Ile Ile Thr Ser Ala Met Lys Glu Lys Ile Tyr Asn
275 280 285
Asn Leu Leu Ala Asn Tyr Glu Lys Ile Ala Thr Arg Leu Ser Arg Val
290 295 300
Asn Ser Ala Pro Pro Glu Tyr Asp Ile Asn Glu Tyr Lys Asp Tyr Phe
305 310 315 320
Gln Trp Lys Tyr Gly Leu Asp Lys Asn Ala Asp Gly Ser Tyr Thr Val
325 330 335
Asn Glu Asn Lys Phe Asn Glu Ile Tyr Lys Lys Leu Tyr Ser Phe Thr
340 345 350
Glu Ile Asp Leu Ala Asn Lys Phe Lys Val Lys Cys Arg Asn Thr Tyr
355 360 365
Phe Ile Lys Tyr Gly Phe Leu Lys Val Pro Asn Leu Leu Asp Asp Asp
370 375 380
Ile Tyr Thr Val Ser Glu Gly Phe Asn Ile Gly Asn Leu Ala Val Asn
385 390 395 400
Asn Arg Gly Gln Asn Ile Lys Leu Asn Pro Lys Ile Ile Asp Ser Ile
405 410 415
Pro Asp Lys Gly Leu Val Glu Lys Ile Val Lys Phe Cys Lys Ser Val
420 425 430
Ile Pro Arg Lys Gly Thr Lys Ala Pro Pro Arg Leu Cys Ile Arg Val
435 440 445
Asn Asn Arg Glu Leu Phe Phe Val Ala Ser Glu Ser Ser Tyr Asn Glu
450 455 460
Asn Asp Ile Asn Thr Pro Lys Glu Ile Asp Asp Thr Thr Asn Leu Asn
465 470 475 480
Asn Asn Tyr Arg Asn Asn Leu Asp Glu Val Ile Leu Asp Tyr Asn Ser
485 490 495
Glu Thr Ile Pro Gln Ile Ser Asn Gln Thr Leu Asn Thr Leu Val Gln
500 505 510
Asp Asp Ser Tyr Val Pro Arg Tyr Asp Ser Asn Gly Thr Ser Glu Ile
515 520 525
Glu Glu His Asn Val Val Asp Leu Asn Val Phe Phe Tyr Leu His Ala
530 535 540
Gln Lys Val Pro Glu Gly Glu Thr Asn Ile Ser Leu Thr Ser Ser Ile
545 550 555 560
Asp Thr Ala Leu Ser Glu Glu Ser Gln Val Tyr Thr Phe Phe Ser Ser
565 570 575
Glu Phe Ile Asn Thr Ile Asn Lys Pro Val His Ala Ala Leu Phe Ile
580 585 590
Ser Trp Ile Asn Gln Val Ile Arg Asp Phe Thr Thr Glu Ala Thr Gln
595 600 605
Lys Ser Thr Phe Asp Lys Ile Ala Asp Ile Ser Leu Val Val Pro Tyr
610 615 620
Val Gly Leu Ala Leu Asn Ile Gly Asn Glu Val Gln Lys Glu Asn Phe
625 630 635 640
Lys Glu Ala Phe Glu Leu Leu Gly Ala Gly Ile Leu Leu Glu Phe Val
645 650 655
Pro Glu Leu Leu Ile Pro Thr Ile Leu Val Phe Thr Ile Lys Ser Phe
660 665 670
Ile Gly Ser Ser Glu Asn Lys Asn Lys Ile Ile Lys Ala Ile Asn Asn
675 680 685
Ser Leu Met Glu Arg Glu Thr Lys Trp Lys Glu Ile Tyr Ser Trp Ile
690 695 700
Val Ser Asn Trp Leu Thr Arg Ile Asn Thr Gln Phe Asn Lys Arg Lys
705 710 715 720
Glu Gln Met Tyr Gln Ala Leu Gln Asn Gln Val Asp Ala Ile Lys Thr
725 730 735
Val Ile Glu Tyr Lys Tyr Asn Asn Tyr Thr Ser Asp Glu Arg Asn Arg
740 745 750
Leu Glu Ser Glu Tyr Asn Ile Asn Asn Ile Arg Glu Glu Leu Asn Lys
755 760 765
Lys Val Ser Leu Ala Met Glu Asn Ile Glu Arg Phe Ile Thr Glu Ser
770 775 780
Ser Ile Phe Tyr Leu Met Lys Leu Ile Asn Glu Ala Lys Val Ser Lys
785 790 795 800
Leu Arg Glu Tyr Asp Glu Gly Val Lys Glu Tyr Leu Leu Asp Tyr Ile
805 810 815
Ser Glu His Arg Ser Ile Leu Gly Asn Ser Val Gln Glu Leu Asn Asp
820 825 830
Leu Val Thr Ser Thr Leu Asn Asn Ser Ile Pro Phe Glu Leu Ser Ser
835 840 845
Tyr Thr Asn Asp Lys Ile Leu Ile Leu Tyr Phe Asn Lys Leu Tyr Lys
850 855 860
Lys Ile Lys Asp Asn Ser Ile Leu Asp Met Arg Tyr Glu Asn Asn Lys
865 870 875 880
Phe Ile Asp Ile Ser Gly Tyr Gly Ser Asn Ile Ser Ile Asn Gly Asp
885 890 895
Val Tyr Ile Tyr Ser Thr Asn Arg Asn Gln Phe Gly Ile Tyr Ser Ser
900 905 910
Lys Pro Ser Glu Val Asn Ile Ala Gln Asn Asn Asp Ile Ile Tyr Asn
915 920 925
Gly Arg Tyr Gln Asn Phe Ser Ile Ser Phe Trp Val Arg Ile Pro Lys
930 935 940
Tyr Phe Asn Lys Val Asn Leu Asn Asn Glu Tyr Thr Ile Ile Asp Cys
945 950 955 960
Ile Arg Asn Asn Asn Ser Gly Trp Lys Ile Ser Leu Asn Tyr Asn Lys
965 970 975
Ile Ile Trp Thr Leu Gln Asp Thr Ala Gly Asn Asn Gln Lys Leu Val
980 985 990
Phe Asn Tyr Thr Gln Met Ile Ser Ile Ser Asp Tyr Ile Asn Lys Trp
995 1000 1005
Ile Phe Val Thr Ile Thr Asn Asn Arg Leu Gly Asn Ser Arg Ile
1010 1015 1020
Tyr Ile Asn Gly Asn Leu Ile Asp Glu Lys Ser Ile Ser Asn Leu
1025 1030 1035
Gly Asp Ile His Val Ser Asp Asn Ile Leu Phe Lys Ile Val Gly
1040 1045 1050
Cys Asn Asp Thr Arg Tyr Val Gly Ile Arg Tyr Phe Lys Val Phe
1055 1060 1065
Asp Thr Glu Leu Gly Lys Thr Glu Ile Glu Thr Leu Tyr Ser Asp
1070 1075 1080
Glu Pro Asp Pro Ser Ile Leu Lys Asp Phe Trp Gly Asn Tyr Leu
1085 1090 1095
Leu Tyr Asn Lys Arg Tyr Tyr Leu Leu Asn Leu Leu Arg Thr Asp
1100 1105 1110
Lys Ser Ile Thr Gln Asn Ser Asn Phe Leu Asn Ile Asn Gln Gln
1115 1120 1125
Arg Gly Val Tyr Gln Lys Pro Asn Ile Phe Ser Asn Thr Arg Leu
1130 1135 1140
Tyr Thr Gly Val Glu Val Ile Ile Arg Lys Asn Gly Ser Thr Asp
1145 1150 1155
Ile Ser Asn Thr Asp Asn Phe Val Arg Lys Asn Asp Leu Ala Tyr
1160 1165 1170
Ile Asn Val Val Asp Arg Asp Val Glu Tyr Arg Leu Tyr Ala Asp
1175 1180 1185
Ile Ser Ile Ala Lys Pro Glu Lys Ile Ile Lys Leu Ile Arg Thr
1190 1195 1200
Ser Asn Ser Asn Asn Ser Leu Gly Gln Ile Ile Val Met Asp Ser
1205 1210 1215
Ile Gly Asn Asn Cys Thr Met Asn Phe Gln Asn Asn Asn Gly Gly
1220 1225 1230
Asn Ile Gly Leu Leu Gly Phe His Ser Asn Asn Leu Val Ala Ser
1235 1240 1245
Ser Trp Tyr Tyr Asn Asn Ile Arg Lys Asn Thr Ser Ser Asn Gly
1250 1255 1260
Cys Phe Trp Ser Phe Ile Ser Lys Glu His Gly Trp Gln Glu Asn
1265 1270 1275
<210> 31
<211> 1297
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa可以是任何天然产生的氨基酸
<400> 31
Met Pro Val Asn Ile Lys Xaa Phe Asn Tyr Asn Asp Pro Ile Asn Asn
1 5 10 15
Asp Asp Ile Ile Met Met Glu Pro Phe Asn Asp Pro Gly Pro Gly Thr
20 25 30
Tyr Tyr Lys Ala Phe Arg Ile Ile Asp Arg Ile Trp Ile Val Pro Glu
35 40 45
Arg Phe Thr Tyr Gly Phe Gln Pro Asp Gln Phe Asn Ala Ser Thr Gly
50 55 60
Val Phe Ser Lys Asp Val Tyr Glu Tyr Tyr Asp Pro Thr Tyr Leu Lys
65 70 75 80
Thr Asp Ala Glu Lys Asp Lys Phe Leu Lys Thr Met Ile Lys Leu Phe
85 90 95
Asn Arg Ile Asn Ser Lys Pro Ser Gly Gln Arg Leu Leu Asp Met Ile
100 105 110
Val Asp Ala Ile Pro Tyr Leu Gly Asn Ala Ser Thr Pro Pro Asp Lys
115 120 125
Phe Ala Ala Asn Val Ala Asn Val Ser Ile Asn Lys Lys Ile Ile Gln
130 135 140
Pro Gly Ala Glu Asp Gln Ile Lys Gly Leu Met Thr Asn Leu Ile Ile
145 150 155 160
Phe Gly Pro Gly Pro Val Leu Ser Asp Asn Phe Thr Asp Ser Met Ile
165 170 175
Met Asn Gly His Ser Pro Ile Ser Glu Gly Phe Gly Ala Arg Met Met
180 185 190
Ile Arg Phe Cys Pro Ser Cys Leu Asn Val Phe Asn Asn Val Gln Glu
195 200 205
Asn Lys Asp Thr Ser Ile Phe Ser Arg Arg Ala Tyr Phe Ala Asp Pro
210 215 220
Ala Leu Thr Leu Met His Glu Leu Ile His Val Leu His Gly Leu Tyr
225 230 235 240
Gly Ile Lys Ile Ser Asn Leu Pro Ile Thr Pro Asn Thr Lys Glu Phe
245 250 255
Phe Met Gln His Ser Asp Pro Val Gln Ala Glu Glu Leu Tyr Thr Phe
260 265 270
Gly Gly His Asp Pro Ser Val Ile Ser Pro Ser Thr Asp Met Asn Ile
275 280 285
Tyr Asn Lys Ala Leu Gln Asn Phe Gln Asp Ile Ala Asn Arg Leu Asn
290 295 300
Ile Val Ser Ser Ala Gln Gly Ser Gly Ile Asp Ile Ser Leu Tyr Lys
305 310 315 320
Gln Ile Tyr Lys Asn Lys Tyr Asp Phe Val Glu Asp Pro Asn Gly Lys
325 330 335
Tyr Ser Val Asp Lys Asp Lys Phe Asp Lys Leu Tyr Lys Ala Leu Met
340 345 350
Phe Gly Phe Thr Glu Thr Asn Leu Ala Gly Glu Tyr Gly Ile Lys Thr
355 360 365
Arg Tyr Ser Tyr Phe Ser Glu Tyr Leu Pro Pro Ile Lys Thr Glu Lys
370 375 380
Leu Leu Asp Asn Thr Ile Tyr Thr Gln Asn Glu Gly Phe Asn Ile Ala
385 390 395 400
Ser Lys Asn Leu Lys Thr Glu Phe Asn Gly Gln Asn Lys Ala Val Asn
405 410 415
Lys Glu Ala Tyr Glu Glu Ile Ser Leu Glu His Leu Val Ile Tyr Arg
420 425 430
Ile Ala Met Cys Lys Pro Val Met Tyr Lys Asn Thr Gly Lys Ser Glu
435 440 445
Gln Cys Ile Ile Val Asn Asn Glu Asp Leu Phe Phe Ile Ala Asn Lys
450 455 460
Asp Ser Phe Ser Lys Asp Leu Ala Lys Ala Glu Thr Ile Ala Tyr Asn
465 470 475 480
Thr Gln Asn Asn Thr Ile Glu Asn Asn Phe Ser Ile Asp Gln Leu Ile
485 490 495
Leu Asp Asn Asp Leu Ser Ser Gly Ile Asp Leu Pro Asn Glu Asn Thr
500 505 510
Glu Pro Phe Thr Asn Phe Asp Asp Ile Asp Ile Pro Val Tyr Ile Lys
515 520 525
Gln Ser Ala Leu Lys Lys Ile Phe Val Asp Gly Asp Ser Leu Phe Glu
530 535 540
Tyr Leu His Ala Gln Thr Phe Pro Ser Asn Ile Glu Asn Leu Gln Leu
545 550 555 560
Thr Asn Ser Leu Asn Asp Ala Leu Arg Asn Asn Asn Lys Val Tyr Thr
565 570 575
Phe Phe Ser Thr Asn Leu Val Glu Lys Ala Asn Thr Val Val Gly Ala
580 585 590
Ser Leu Phe Val Asn Trp Val Lys Gly Val Ile Asp Asp Phe Thr Ser
595 600 605
Glu Ser Thr Gln Lys Ser Thr Ile Asp Lys Val Ser Asp Val Ser Ile
610 615 620
Ile Ile Pro Tyr Ile Gly Pro Ala Leu Asn Val Gly Asn Glu Thr Ala
625 630 635 640
Lys Glu Asn Phe Lys Asn Ala Phe Glu Ile Gly Gly Ala Ala Ile Leu
645 650 655
Met Glu Phe Ile Pro Glu Leu Ile Val Pro Ile Val Gly Phe Phe Thr
660 665 670
Leu Glu Ser Tyr Val Gly Asn Lys Gly His Ile Ile Met Thr Ile Ser
675 680 685
Asn Ala Leu Lys Lys Arg Asp Gln Lys Trp Thr Asp Met Tyr Gly Leu
690 695 700
Ile Val Ser Gln Trp Leu Ser Thr Val Asn Thr Gln Phe Tyr Thr Ile
705 710 715 720
Lys Glu Arg Met Tyr Asn Ala Leu Asn Asn Gln Ser Gln Ala Ile Glu
725 730 735
Lys Ile Ile Glu Asp Gln Tyr Asn Arg Tyr Ser Glu Glu Asp Lys Met
740 745 750
Asn Ile Asn Ile Asp Phe Asn Asp Ile Asp Phe Lys Leu Asn Gln Ser
755 760 765
Ile Asn Leu Ala Ile Asn Asn Ile Asp Asp Phe Ile Asn Gln Cys Ser
770 775 780
Ile Ser Tyr Leu Met Asn Arg Met Ile Pro Leu Ala Val Lys Lys Leu
785 790 795 800
Lys Asp Phe Asp Asp Asn Leu Lys Arg Asp Leu Leu Glu Tyr Ile Asp
805 810 815
Thr Asn Glu Leu Tyr Leu Leu Asp Glu Val Asn Ile Leu Lys Ser Lys
820 825 830
Val Asn Arg His Leu Lys Asp Ser Ile Pro Phe Asp Leu Ser Leu Tyr
835 840 845
Thr Lys Asp Thr Ile Leu Ile Gln Val Phe Asn Asn Tyr Ile Ser Asn
850 855 860
Ile Ser Ser Asn Ala Ile Leu Ser Leu Ser Tyr Arg Gly Gly Arg Leu
865 870 875 880
Ile Asp Ser Ser Gly Tyr Gly Ala Thr Met Asn Val Gly Ser Asp Val
885 890 895
Ile Phe Asn Asp Ile Gly Asn Gly Gln Phe Lys Leu Asn Asn Ser Glu
900 905 910
Asn Ser Asn Ile Thr Ala His Gln Ser Lys Phe Val Val Tyr Asp Ser
915 920 925
Met Phe Asp Asn Phe Ser Ile Asn Phe Trp Val Arg Thr Pro Lys Tyr
930 935 940
Asn Asn Asn Asp Ile Gln Thr Tyr Leu Gln Asn Glu Tyr Thr Ile Ile
945 950 955 960
Ser Cys Ile Lys Asn Asp Ser Gly Trp Lys Val Ser Ile Lys Gly Asn
965 970 975
Arg Ile Ile Trp Thr Leu Ile Asp Val Asn Ala Lys Ser Lys Ser Ile
980 985 990
Phe Phe Glu Tyr Ser Ile Lys Asp Asn Ile Ser Asp Tyr Ile Asn Lys
995 1000 1005
Trp Phe Ser Ile Thr Ile Thr Asn Asp Arg Leu Gly Asn Ala Asn
1010 1015 1020
Ile Tyr Ile Asn Gly Ser Leu Lys Lys Ser Glu Lys Ile Leu Asn
1025 1030 1035
Leu Asp Arg Ile Asn Ser Ser Asn Asp Ile Asp Phe Lys Leu Ile
1040 1045 1050
Asn Cys Thr Asp Thr Thr Lys Phe Val Trp Ile Lys Asp Phe Asn
1055 1060 1065
Ile Phe Gly Arg Glu Leu Asn Ala Thr Glu Val Ser Ser Leu Tyr
1070 1075 1080
Trp Ile Gln Ser Ser Thr Asn Thr Leu Lys Asp Phe Trp Gly Asn
1085 1090 1095
Pro Leu Arg Tyr Asp Thr Gln Tyr Tyr Leu Phe Asn Gln Gly Met
1100 1105 1110
Gln Asn Ile Tyr Ile Lys Tyr Phe Ser Lys Ala Ser Met Gly Glu
1115 1120 1125
Thr Ala Pro Arg Thr Asn Phe Asn Asn Ala Ala Ile Asn Tyr Gln
1130 1135 1140
Asn Leu Tyr Leu Gly Leu Arg Phe Ile Ile Lys Lys Ala Ser Asn
1145 1150 1155
Ser Arg Asn Ile Asn Asn Asp Asn Ile Val Arg Glu Gly Asp Tyr
1160 1165 1170
Ile Tyr Leu Asn Ile Asp Asn Ile Ser Asp Glu Ser Tyr Arg Val
1175 1180 1185
Tyr Val Leu Val Asn Ser Lys Glu Ile Gln Thr Gln Leu Phe Leu
1190 1195 1200
Ala Pro Ile Asn Asp Asp Pro Thr Phe Tyr Asp Val Leu Gln Ile
1205 1210 1215
Lys Lys Tyr Tyr Glu Lys Thr Thr Tyr Asn Cys Gln Ile Leu Cys
1220 1225 1230
Glu Lys Asp Thr Lys Thr Phe Gly Leu Phe Gly Ile Gly Lys Phe
1235 1240 1245
Val Lys Asp Tyr Gly Tyr Val Trp Asp Thr Tyr Asp Asn Tyr Phe
1250 1255 1260
Cys Ile Ser Gln Trp Tyr Leu Arg Arg Ile Ser Glu Asn Ile Asn
1265 1270 1275
Lys Leu Arg Leu Gly Cys Asn Trp Gln Phe Ile Pro Val Asp Glu
1280 1285 1290
Gly Trp Thr Glu
1295
<210> 32
<211> 1306
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 32
Met Lys Leu Glu Ile Asn Lys Phe Asn Tyr Asn Asp Pro Ile Asp Gly
1 5 10 15
Ile Asn Val Ile Thr Met Arg Pro Pro Arg His Ser Asp Lys Ile Asn
20 25 30
Lys Gly Lys Gly Pro Phe Lys Ala Phe Gln Val Ile Lys Asn Ile Trp
35 40 45
Ile Val Pro Glu Arg Tyr Asn Phe Thr Asn Asn Thr Asn Asp Leu Asn
50 55 60
Ile Pro Ser Glu Pro Ile Met Glu Ala Asp Ala Ile Tyr Asn Pro Asn
65 70 75 80
Tyr Leu Asn Thr Pro Ser Glu Lys Asp Glu Phe Leu Gln Gly Val Ile
85 90 95
Lys Val Leu Glu Arg Ile Lys Ser Lys Pro Glu Gly Glu Lys Leu Leu
100 105 110
Glu Leu Ile Ser Ser Ser Ile Pro Leu Pro Leu Val Ser Asn Gly Ala
115 120 125
Leu Thr Leu Ser Asp Asn Glu Thr Ile Ala Tyr Gln Glu Asn Asn Asn
130 135 140
Ile Val Ser Asn Leu Gln Ala Asn Leu Val Ile Tyr Gly Pro Gly Pro
145 150 155 160
Asp Ile Ala Asn Asn Ala Thr Tyr Gly Leu Tyr Ser Thr Pro Ile Ser
165 170 175
Asn Gly Glu Gly Thr Leu Ser Glu Val Ser Phe Ser Pro Phe Tyr Leu
180 185 190
Lys Pro Phe Asp Glu Ser Tyr Gly Asn Tyr Arg Ser Leu Val Asn Ile
195 200 205
Val Asn Lys Phe Val Lys Arg Glu Phe Ala Pro Asp Pro Ala Ser Thr
210 215 220
Leu Met His Glu Leu Val His Val Thr His Asn Leu Tyr Gly Ile Ser
225 230 235 240
Asn Arg Asn Phe Tyr Tyr Asn Phe Asp Thr Gly Lys Ile Glu Thr Ser
245 250 255
Arg Gln Gln Asn Ser Leu Ile Phe Glu Glu Leu Leu Thr Phe Gly Gly
260 265 270
Ile Asp Ser Lys Ala Ile Ser Ser Leu Ile Ile Lys Lys Ile Ile Glu
275 280 285
Thr Ala Lys Asn Asn Tyr Thr Thr Leu Ile Ser Glu Arg Leu Asn Thr
290 295 300
Val Thr Val Glu Asn Asp Leu Leu Lys Tyr Ile Lys Asn Lys Ile Pro
305 310 315 320
Val Gln Gly Arg Leu Gly Asn Phe Lys Leu Asp Thr Ala Glu Phe Glu
325 330 335
Lys Lys Leu Asn Thr Ile Leu Phe Val Leu Asn Glu Ser Asn Leu Ala
340 345 350
Gln Arg Phe Ser Ile Leu Val Arg Lys His Tyr Leu Lys Glu Arg Pro
355 360 365
Ile Asp Pro Ile Tyr Val Asn Ile Leu Asp Asp Asn Ser Tyr Ser Thr
370 375 380
Leu Glu Gly Phe Asn Ile Ser Ser Gln Gly Ser Asn Asp Phe Gln Gly
385 390 395 400
Gln Leu Leu Glu Ser Ser Tyr Phe Glu Lys Ile Glu Ser Asn Ala Leu
405 410 415
Arg Ala Phe Ile Lys Ile Cys Pro Arg Asn Gly Leu Leu Tyr Asn Ala
420 425 430
Ile Tyr Arg Asn Ser Lys Asn Tyr Leu Asn Asn Ile Asp Leu Glu Asp
435 440 445
Lys Lys Thr Thr Ser Lys Thr Asn Val Ser Tyr Pro Cys Ser Leu Leu
450 455 460
Asn Gly Cys Ile Glu Val Glu Asn Lys Asp Leu Phe Leu Ile Ser Asn
465 470 475 480
Lys Asp Ser Leu Asn Asp Ile Asn Leu Ser Glu Glu Lys Ile Lys Pro
485 490 495
Glu Thr Thr Val Phe Phe Lys Asp Lys Leu Pro Pro Gln Asp Ile Thr
500 505 510
Leu Ser Asn Tyr Asp Phe Thr Glu Ala Asn Ser Ile Pro Ser Ile Ser
515 520 525
Gln Gln Asn Ile Leu Glu Arg Asn Glu Glu Leu Tyr Glu Pro Ile Arg
530 535 540
Asn Ser Leu Phe Glu Ile Lys Thr Ile Tyr Val Asp Lys Leu Thr Thr
545 550 555 560
Phe His Phe Leu Glu Ala Gln Asn Ile Asp Glu Ser Ile Asp Ser Ser
565 570 575
Lys Ile Arg Val Glu Leu Thr Asp Ser Val Asp Glu Ala Leu Ser Asn
580 585 590
Pro Asn Lys Val Tyr Ser Pro Phe Lys Asn Met Ser Asn Thr Ile Asn
595 600 605
Ser Ile Glu Thr Gly Ile Thr Ser Thr Tyr Ile Phe Tyr Gln Trp Leu
610 615 620
Arg Ser Ile Val Lys Asp Phe Ser Asp Glu Thr Gly Lys Ile Asp Val
625 630 635 640
Ile Asp Lys Ser Ser Asp Thr Leu Ala Ile Val Pro Tyr Ile Gly Pro
645 650 655
Leu Leu Asn Ile Gly Asn Asp Ile Arg His Gly Asp Phe Val Gly Ala
660 665 670
Ile Glu Leu Ala Gly Ile Thr Ala Leu Leu Glu Tyr Val Pro Glu Phe
675 680 685
Thr Ile Pro Ile Leu Val Gly Leu Glu Val Ile Gly Gly Glu Leu Ala
690 695 700
Arg Glu Gln Val Glu Ala Ile Val Asn Asn Ala Leu Asp Lys Arg Asp
705 710 715 720
Gln Lys Trp Ala Glu Val Tyr Asn Ile Thr Lys Ala Gln Trp Trp Gly
725 730 735
Thr Ile His Leu Gln Ile Asn Thr Arg Leu Ala His Thr Tyr Lys Ala
740 745 750
Leu Ser Arg Gln Ala Asn Ala Ile Lys Met Asn Met Glu Phe Gln Leu
755 760 765
Ala Asn Tyr Lys Gly Asn Ile Asp Asp Lys Ala Lys Ile Lys Asn Ala
770 775 780
Ile Ser Glu Thr Glu Ile Leu Leu Asn Lys Ser Val Glu Gln Ala Met
785 790 795 800
Lys Asn Thr Glu Lys Phe Met Ile Lys Leu Ser Asn Ser Tyr Leu Thr
805 810 815
Lys Glu Met Ile Pro Lys Val Gln Asp Asn Leu Lys Asn Phe Asp Leu
820 825 830
Glu Thr Lys Lys Thr Leu Asp Lys Phe Ile Lys Glu Lys Glu Asp Ile
835 840 845
Leu Gly Thr Asn Leu Ser Ser Ser Leu Arg Arg Lys Val Ser Ile Arg
850 855 860
Leu Asn Lys Asn Ile Ala Phe Asp Ile Asn Asp Ile Pro Phe Ser Glu
865 870 875 880
Phe Asp Asp Leu Ile Asn Gln Tyr Lys Asn Glu Ile Glu Asp Tyr Glu
885 890 895
Val Leu Asn Leu Gly Ala Glu Asp Gly Lys Ile Lys Asp Leu Ser Gly
900 905 910
Thr Thr Ser Asp Ile Asn Ile Gly Ser Asp Ile Glu Leu Ala Asp Gly
915 920 925
Arg Glu Asn Lys Ala Ile Lys Ile Lys Gly Ser Glu Asn Ser Thr Ile
930 935 940
Lys Ile Ala Met Asn Lys Tyr Leu Arg Phe Ser Ala Thr Asp Asn Phe
945 950 955 960
Ser Ile Ser Phe Trp Ile Lys His Pro Lys Pro Thr Asn Leu Leu Asn
965 970 975
Asn Gly Ile Glu Tyr Thr Leu Val Glu Asn Phe Asn Gln Arg Gly Trp
980 985 990
Lys Ile Ser Ile Gln Asp Ser Lys Leu Ile Trp Tyr Leu Arg Asp His
995 1000 1005
Asn Asn Ser Ile Lys Ile Val Thr Pro Asp Tyr Ile Ala Phe Asn
1010 1015 1020
Gly Trp Asn Leu Ile Thr Ile Thr Asn Asn Arg Ser Lys Gly Ser
1025 1030 1035
Ile Val Tyr Val Asn Gly Ser Lys Ile Glu Glu Lys Asp Ile Ser
1040 1045 1050
Ser Ile Trp Asn Thr Glu Val Asp Asp Pro Ile Ile Phe Arg Leu
1055 1060 1065
Lys Asn Asn Arg Asp Thr Gln Ala Phe Thr Leu Leu Asp Gln Phe
1070 1075 1080
Ser Ile Tyr Arg Lys Glu Leu Asn Gln Asn Glu Val Val Lys Leu
1085 1090 1095
Tyr Asn Tyr Tyr Phe Asn Ser Asn Tyr Ile Arg Asp Ile Trp Gly
1100 1105 1110
Asn Pro Leu Gln Tyr Asn Lys Lys Tyr Tyr Leu Gln Thr Gln Asp
1115 1120 1125
Lys Pro Gly Lys Gly Leu Ile Arg Glu Tyr Trp Ser Ser Phe Gly
1130 1135 1140
Tyr Asp Tyr Val Ile Leu Ser Asp Ser Lys Thr Ile Thr Phe Pro
1145 1150 1155
Asn Asn Ile Arg Tyr Gly Ala Leu Tyr Asn Gly Ser Lys Val Leu
1160 1165 1170
Ile Lys Asn Ser Lys Lys Leu Asp Gly Leu Val Arg Asn Lys Asp
1175 1180 1185
Phe Ile Gln Leu Glu Ile Asp Gly Tyr Asn Met Gly Ile Ser Ala
1190 1195 1200
Asp Arg Phe Asn Glu Asp Thr Asn Tyr Ile Gly Thr Thr Tyr Gly
1205 1210 1215
Thr Thr His Asp Leu Thr Thr Asp Phe Glu Ile Ile Gln Arg Gln
1220 1225 1230
Glu Lys Tyr Arg Asn Tyr Cys Gln Leu Lys Thr Pro Tyr Asn Ile
1235 1240 1245
Phe His Lys Ser Gly Leu Met Ser Thr Glu Thr Ser Lys Pro Thr
1250 1255 1260
Phe His Asp Tyr Arg Asp Trp Val Tyr Ser Ser Ala Trp Tyr Phe
1265 1270 1275
Gln Asn Tyr Glu Asn Leu Asn Leu Arg Lys His Thr Lys Thr Asn
1280 1285 1290
Trp Tyr Phe Ile Pro Lys Asp Glu Gly Trp Asp Glu Asp
1295 1300 1305
<210> 33
<211> 1315
<212> PRT
<213> 破伤风梭菌（Clostridium tetani）
<400> 33
Met Pro Ile Thr Ile Asn Asn Phe Arg Tyr Ser Asp Pro Val Asn Asn
1 5 10 15
Asp Thr Ile Ile Met Met Glu Pro Pro Tyr Cys Lys Gly Leu Asp Ile
20 25 30
Tyr Tyr Lys Ala Phe Lys Ile Thr Asp Arg Ile Trp Ile Val Pro Glu
35 40 45
Arg Tyr Glu Phe Gly Thr Lys Pro Glu Asp Phe Asn Pro Pro Ser Ser
50 55 60
Leu Ile Glu Gly Ala Ser Glu Tyr Tyr Asp Pro Asn Tyr Leu Arg Thr
65 70 75 80
Asp Ser Asp Lys Asp Arg Phe Leu Gln Thr Met Val Lys Leu Phe Asn
85 90 95
Arg Ile Lys Asn Asn Val Ala Gly Glu Ala Leu Leu Asp Lys Ile Ile
100 105 110
Asn Ala Ile Pro Tyr Leu Gly Asn Ser Tyr Ser Leu Leu Asp Lys Phe
115 120 125
Asp Thr Asn Ser Asn Ser Val Ser Phe Asn Leu Leu Glu Gln Asp Pro
130 135 140
Ser Gly Ala Thr Thr Lys Ser Ala Met Leu Thr Asn Leu Ile Ile Phe
145 150 155 160
Gly Pro Gly Pro Val Leu Asn Lys Asn Glu Val Arg Gly Ile Val Leu
165 170 175
Arg Val Asp Asn Lys Asn Tyr Phe Pro Cys Arg Asp Gly Phe Gly Ser
180 185 190
Ile Met Gln Met Ala Phe Cys Pro Glu Tyr Val Pro Thr Phe Asp Asn
195 200 205
Val Ile Glu Asn Ile Thr Ser Leu Thr Ile Gly Lys Ser Lys Tyr Phe
210 215 220
Gln Asp Pro Ala Leu Leu Leu Met His Glu Leu Ile His Val Leu His
225 230 235 240
Gly Leu Tyr Gly Met Gln Val Ser Ser His Glu Ile Ile Pro Ser Lys
245 250 255
Gln Glu Ile Tyr Met Gln His Thr Tyr Pro Ile Ser Ala Glu Glu Leu
260 265 270
Phe Thr Phe Gly Gly Gln Asp Ala Asn Leu Ile Ser Ile Asp Ile Lys
275 280 285
Asn Asp Leu Tyr Glu Lys Thr Leu Asn Asp Tyr Lys Ala Ile Ala Asn
290 295 300
Lys Leu Ser Gln Val Thr Ser Cys Asn Asp Pro Asn Ile Asp Ile Asp
305 310 315 320
Ser Tyr Lys Gln Ile Tyr Gln Gln Lys Tyr Gln Phe Asp Lys Asp Ser
325 330 335
Asn Gly Gln Tyr Ile Val Asn Glu Asp Lys Phe Gln Ile Leu Tyr Asn
340 345 350
Ser Ile Met Tyr Gly Phe Thr Glu Ile Glu Leu Gly Lys Lys Phe Asn
355 360 365
Ile Lys Thr Arg Leu Ser Tyr Phe Ser Met Asn His Asp Pro Val Lys
370 375 380
Ile Pro Asn Leu Leu Asp Asp Thr Ile Tyr Asn Asp Thr Glu Gly Phe
385 390 395 400
Asn Ile Glu Ser Lys Asp Leu Lys Ser Glu Tyr Lys Gly Gln Asn Met
405 410 415
Arg Val Asn Thr Asn Ala Phe Arg Asn Val Asp Gly Ser Gly Leu Val
420 425 430
Ser Lys Leu Ile Gly Leu Cys Lys Lys Ile Ile Pro Pro Thr Asn Ile
435 440 445
Arg Glu Asn Leu Tyr Asn Arg Thr Ala Ser Leu Thr Asp Leu Gly Gly
450 455 460
Glu Leu Cys Ile Lys Ile Lys Asn Glu Asp Leu Thr Phe Ile Ala Glu
465 470 475 480
Lys Asn Ser Phe Ser Glu Glu Pro Phe Gln Asp Glu Ile Val Ser Tyr
485 490 495
Asn Thr Lys Asn Lys Pro Leu Asn Phe Asn Tyr Ser Leu Asp Lys Ile
500 505 510
Ile Val Asp Tyr Asn Leu Gln Ser Lys Ile Thr Leu Pro Asn Asp Arg
515 520 525
Thr Thr Pro Val Thr Lys Gly Ile Pro Tyr Ala Pro Glu Tyr Lys Ser
530 535 540
Asn Ala Ala Ser Thr Ile Glu Ile His Asn Ile Asp Asp Asn Thr Ile
545 550 555 560
Tyr Gln Tyr Leu Tyr Ala Gln Lys Ser Pro Thr Thr Leu Gln Arg Ile
565 570 575
Thr Met Thr Asn Ser Val Asp Asp Ala Leu Ile Asn Ser Thr Lys Ile
580 585 590
Tyr Ser Tyr Phe Pro Ser Val Ile Ser Lys Val Asn Gln Gly Ala Gln
595 600 605
Gly Ile Leu Phe Leu Gln Trp Val Arg Asp Ile Ile Asp Asp Phe Thr
610 615 620
Asn Glu Ser Ser Gln Lys Thr Thr Ile Asp Lys Ile Ser Asp Val Ser
625 630 635 640
Thr Ile Val Pro Tyr Ile Gly Pro Ala Leu Asn Ile Val Lys Gln Gly
645 650 655
Tyr Glu Gly Asn Phe Ile Gly Ala Leu Glu Thr Thr Gly Val Val Leu
660 665 670
Leu Leu Glu Tyr Ile Pro Glu Ile Thr Leu Pro Val Ile Ala Ala Leu
675 680 685
Ser Ile Ala Glu Ser Ser Thr Gln Lys Glu Lys Ile Ile Lys Thr Ile
690 695 700
Asp Asn Phe Leu Glu Lys Arg Tyr Glu Lys Trp Ile Glu Val Tyr Lys
705 710 715 720
Leu Val Lys Ala Lys Trp Leu Gly Thr Val Asn Thr Gln Phe Gln Lys
725 730 735
Arg Ser Tyr Gln Met Tyr Arg Ser Leu Glu Tyr Gln Val Asp Ala Ile
740 745 750
Lys Lys Ile Ile Asp Tyr Glu Tyr Lys Ile Tyr Ser Gly Pro Asp Lys
755 760 765
Glu Gln Ile Ala Asp Glu Ile Asn Asn Leu Lys Asn Lys Leu Glu Glu
770 775 780
Lys Ala Asn Lys Ala Met Ile Asn Ile Asn Ile Phe Met Arg Glu Ser
785 790 795 800
Ser Arg Ser Phe Leu Val Asn Gln Met Ile Asn Glu Ala Lys Lys Gln
805 810 815
Leu Leu Glu Phe Asp Thr Gln Ser Lys Asn Ile Leu Met Gln Tyr Ile
820 825 830
Lys Ala Asn Ser Lys Phe Ile Gly Ile Thr Glu Leu Lys Lys Leu Glu
835 840 845
Ser Lys Ile Asn Lys Val Phe Ser Thr Pro Ile Pro Phe Ser Tyr Ser
850 855 860
Lys Asn Leu Asp Cys Trp Val Asp Asn Glu Glu Asp Ile Asp Val Ile
865 870 875 880
Leu Lys Lys Ser Thr Ile Leu Asn Leu Asp Ile Asn Asn Asp Ile Ile
885 890 895
Ser Asp Ile Ser Gly Phe Asn Ser Ser Val Ile Thr Tyr Pro Asp Ala
900 905 910
Gln Leu Val Pro Gly Ile Asn Gly Lys Ala Ile His Leu Val Asn Asn
915 920 925
Glu Ser Ser Glu Val Ile Val His Lys Ala Met Asp Ile Glu Tyr Asn
930 935 940
Asp Met Phe Asn Asn Phe Thr Val Ser Phe Trp Leu Arg Val Pro Lys
945 950 955 960
Val Ser Ala Ser His Leu Glu Gln Tyr Gly Thr Asn Glu Tyr Ser Ile
965 970 975
Ile Ser Ser Met Lys Lys His Ser Leu Ser Ile Gly Ser Gly Trp Ser
980 985 990
Val Ser Leu Lys Gly Asn Asn Leu Ile Trp Thr Leu Lys Asp Ser Ala
995 1000 1005
Gly Glu Val Arg Gln Ile Thr Phe Arg Asp Leu Pro Asp Lys Phe
1010 1015 1020
Asn Ala Tyr Leu Ala Asn Lys Trp Val Phe Ile Thr Ile Thr Asn
1025 1030 1035
Asp Arg Leu Ser Ser Ala Asn Leu Tyr Ile Asn Gly Val Leu Met
1040 1045 1050
Gly Ser Ala Glu Ile Thr Gly Leu Gly Ala Ile Arg Glu Asp Asn
1055 1060 1065
Asn Ile Thr Leu Lys Leu Asp Arg Cys Asn Asn Asn Asn Gln Tyr
1070 1075 1080
Val Ser Ile Asp Lys Phe Arg Ile Phe Cys Lys Ala Leu Asn Pro
1085 1090 1095
Lys Glu Ile Glu Lys Leu Tyr Thr Ser Tyr Leu Ser Ile Thr Phe
1100 1105 1110
Leu Arg Asp Phe Trp Gly Asn Pro Leu Arg Tyr Asp Thr Glu Tyr
1115 1120 1125
Tyr Leu Ile Pro Val Ala Ser Ser Ser Lys Asp Val Gln Leu Lys
1130 1135 1140
Asn Ile Thr Asp Tyr Met Tyr Leu Thr Asn Ala Pro Ser Tyr Thr
1145 1150 1155
Asn Gly Lys Leu Asn Ile Tyr Tyr Arg Arg Leu Tyr Asn Gly Leu
1160 1165 1170
Lys Phe Ile Ile Lys Arg Tyr Thr Pro Asn Asn Glu Ile Asp Ser
1175 1180 1185
Phe Val Lys Ser Gly Asp Phe Ile Lys Leu Tyr Val Ser Tyr Asn
1190 1195 1200
Asn Asn Glu His Ile Val Gly Tyr Pro Lys Asp Gly Asn Ala Phe
1205 1210 1215
Asn Asn Leu Asp Arg Ile Leu Arg Val Gly Tyr Asn Ala Pro Gly
1220 1225 1230
Ile Pro Leu Tyr Lys Lys Met Glu Ala Val Lys Leu Arg Asp Leu
1235 1240 1245
Lys Thr Tyr Ser Val Gln Leu Lys Leu Tyr Asp Asp Lys Asn Ala
1250 1255 1260
Ser Leu Gly Leu Val Gly Thr His Asn Gly Gln Ile Gly Asn Asp
1265 1270 1275
Pro Asn Arg Asp Ile Leu Ile Ala Ser Asn Trp Tyr Phe Asn His
1280 1285 1290
Leu Lys Asp Lys Ile Leu Gly Cys Asp Trp Tyr Phe Val Pro Thr
1295 1300 1305
Asp Glu Gly Trp Thr Asn Asp
1310 1315
<210> 34
<211> 14
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 34
Cys Leu Arg Leu Thr Lys Asn Ser Arg Asp Asp Ser Thr Cys
1 5 10
<210> 35
<211> 14
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 35
Cys Leu Arg Leu Thr Arg Asn Ser Arg Asp Asp Ser Thr Cys
1 5 10
<210> 36
<211> 17
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 36
Cys His Lys Ala Ile Asp Gly Arg Ser Leu Tyr Asn Lys Thr Leu Asp
1 5 10 15
Cys
<210> 37
<211> 25
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 37
Cys Val Arg Gly Ile Ile Thr Ser Lys Thr Lys Ser Leu Asp Glu Gly
1 5 10 15
Tyr Asn Lys Ala Leu Asn Glu Leu Cys
20 25
<210> 38
<211> 25
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 38
Cys Val Arg Gly Ile Ile Thr Ser Lys Thr Lys Ser Leu Asp Glu Gly
1 5 10 15
Tyr Asn Lys Ala Leu Asn Asp Leu Cys
20 25
<210> 39
<211> 25
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 39
Cys Val Arg Gly Ile Ile Thr Ser Lys Thr Lys Ser Leu Asp Lys Gly
1 5 10 15
Tyr Asn Lys Ala Leu Asn Asp Leu Cys
20 25
<210> 40
<211> 25
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 40
Cys Val Arg Gly Ile Ile Pro Phe Lys Thr Lys Ser Leu Asp Glu Gly
1 5 10 15
Tyr Asn Lys Ala Leu Asn Tyr Leu Cys
20 25
<210> 41
<211> 25
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 41
Cys Val Arg Gly Ile Ile Pro Phe Lys Thr Lys Ser Leu Asp Glu Gly
1 5 10 15
Tyr Asn Lys Ala Leu Asn Asp Leu Cys
20 25
<210> 42
<211> 11
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 42
Cys Ser Asn Ser Asn Thr Lys Asn Ser Leu Cys
1 5 10
<210> 43
<211> 15
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 43
Cys Lys Asn Ile Val Ser Val Lys Gly Ile Arg Lys Ser Ile Cys
1 5 10 15
<210> 44
<211> 15
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 44
Cys Thr Asn Ile Phe Ser Pro Lys Gly Ile Arg Lys Ser Ile Cys
1 5 10 15
<210> 45
<211> 15
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 45
Cys Lys Asn Ile Val Phe Ser Lys Gly Ile Thr Lys Ser Ile Cys
1 5 10 15
<210> 46
<211> 15
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 46
Cys Lys Asn Ile Val Phe Ser Lys Gly Ile Arg Lys Ser Ile Cys
1 5 10 15
<210> 47
<211> 15
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 47
Cys Lys Ser Ile Val Ser Lys Lys Gly Thr Lys Asn Ser Leu Cys
1 5 10 15
<210> 48
<211> 15
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 48
Cys Leu Asn Ser Ser Phe Lys Lys Asn Thr Lys Lys Pro Leu Cys
1 5 10 15
<210> 49
<211> 17
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 49
Cys Lys Ser Val Ile Pro Arg Lys Gly Thr Lys Ala Pro Pro Arg Leu
1 5 10 15
Cys
<210> 50
<211> 17
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 50
Cys Lys Ser Ile Ile Pro Arg Lys Gly Thr Lys Ala Pro Pro Arg Leu
1 5 10 15
Cys
<210> 51
<211> 17
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 51
Cys Lys Ser Ile Ile Pro Arg Lys Gly Thr Lys Gln Ser Pro Ser Leu
1 5 10 15
Cys
<210> 52
<211> 29
<212> PRT
<213> 破伤风梭菌（Clostridium tetani）
<400> 52
Cys Lys Lys Ile Ile Pro Pro Thr Asn Ile Arg Glu Asn Leu Tyr Asn
1 5 10 15
Arg Thr Ala Ser Leu Thr Asp Leu Gly Gly Glu Leu Cys
20 25
<210> 53
<211> 15
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 53
Cys Lys Pro Val Met Tyr Lys Asn Thr Gly Lys Ser Glu Gln Cys
1 5 10 15
<210> 54
<211> 10
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 54
Cys Lys Ser Val Lys Val Pro Gly Ile Cys
1 5 10
<210> 55
<211> 10
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 55
Cys Lys Ser Val Arg Ala Pro Gly Ile Cys
1 5 10
<210> 56
<211> 10
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 56
Cys Lys Ser Val Lys Ala Pro Gly Ile Cys
1 5 10
<210> 57
<211> 45
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 57
Cys Pro Arg Asn Gly Leu Leu Tyr Asn Ala Ile Tyr Arg Asn Ser Lys
1 5 10 15
Asn Tyr Leu Asn Asn Ile Asp Leu Glu Asp Lys Lys Thr Thr Ser Lys
20 25 30
Thr Asn Val Ser Tyr Pro Cys Ser Leu Leu Asn Gly Cys
35 40 45
<210> 58
<211> 5
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<220>
<221> misc_feature
<222> (3)..(4)
<223> Xaa可以是任何天然产生的氨基酸
<400> 58
His Glu Xaa Xaa His
1 5
<210> 59
<211> 794
<212> PRT
<213> 智人（Homo sapiens）
<400> 59
Met Glu Leu Arg Pro Trp Leu Leu Trp Val Val Ala Ala Thr Gly Thr
1 5 10 15
Leu Val Leu Leu Ala Ala Asp Ala Gln Gly Gln Lys Val Phe Thr Asn
20 25 30
Thr Trp Ala Val Arg Ile Pro Gly Gly Pro Ala Val Ala Asn Ser Val
35 40 45
Ala Arg Lys His Gly Phe Leu Asn Leu Gly Gln Ile Phe Gly Asp Tyr
50 55 60
Tyr His Phe Trp His Arg Gly Val Thr Lys Arg Ser Leu Ser Pro His
65 70 75 80
Arg Pro Arg His Ser Arg Leu Gln Arg Glu Pro Gln Val Gln Trp Leu
85 90 95
Glu Gln Gln Val Ala Lys Arg Arg Thr Lys Arg Asp Val Tyr Gln Glu
100 105 110
Pro Thr Asp Pro Lys Phe Pro Gln Gln Trp Tyr Leu Ser Gly Val Thr
115 120 125
Gln Arg Asp Leu Asn Val Lys Ala Ala Trp Ala Gln Gly Tyr Thr Gly
130 135 140
His Gly Ile Val Val Ser Ile Leu Asp Asp Gly Ile Glu Lys Asn His
145 150 155 160
Pro Asp Leu Ala Gly Asn Tyr Asp Pro Gly Ala Ser Phe Asp Val Asn
165 170 175
Asp Gln Asp Pro Asp Pro Gln Pro Arg Tyr Thr Gln Met Asn Asp Asn
180 185 190
Arg His Gly Thr Arg Cys Ala Gly Glu Val Ala Ala Val Ala Asn Asn
195 200 205
Gly Val Cys Gly Val Gly Val Ala Tyr Asn Ala Arg Ile Gly Gly Val
210 215 220
Arg Met Leu Asp Gly Glu Val Thr Asp Ala Val Glu Ala Arg Ser Leu
225 230 235 240
Gly Leu Asn Pro Asn His Ile His Ile Tyr Ser Ala Ser Trp Gly Pro
245 250 255
Glu Asp Asp Gly Lys Thr Val Asp Gly Pro Ala Arg Leu Ala Glu Glu
260 265 270
Ala Phe Phe Arg Gly Val Ser Gln Gly Arg Gly Gly Leu Gly Ser Ile
275 280 285
Phe Val Trp Ala Ser Gly Asn Gly Gly Arg Glu His Asp Ser Cys Asn
290 295 300
Cys Asp Gly Tyr Thr Asn Ser Ile Tyr Thr Leu Ser Ile Ser Ser Ala
305 310 315 320
Thr Gln Phe Gly Asn Val Pro Trp Tyr Ser Glu Ala Cys Ser Ser Thr
325 330 335
Leu Ala Thr Thr Tyr Ser Ser Gly Asn Gln Asn Glu Lys Gln Ile Val
340 345 350
Thr Thr Asp Leu Arg Gln Lys Cys Thr Glu Ser His Thr Gly Thr Ser
355 360 365
Ala Ser Ala Pro Leu Ala Ala Gly Ile Ile Ala Leu Thr Leu Glu Ala
370 375 380
Asn Lys Asn Leu Thr Trp Arg Asp Met Gln His Leu Val Val Gln Thr
385 390 395 400
Ser Lys Pro Ala His Leu Asn Ala Asn Asp Trp Ala Thr Asn Gly Val
405 410 415
Gly Arg Lys Val Ser His Ser Tyr Gly Tyr Gly Leu Leu Asp Ala Gly
420 425 430
Ala Met Val Ala Leu Ala Gln Asn Trp Thr Thr Val Ala Pro Gln Arg
435 440 445
Lys Cys Ile Ile Asp Ile Leu Thr Glu Pro Lys Asp Ile Gly Lys Arg
450 455 460
Leu Glu Val Arg Lys Thr Val Thr Ala Cys Leu Gly Glu Pro Asn His
465 470 475 480
Ile Thr Arg Leu Glu His Ala Gln Ala Arg Leu Thr Leu Ser Tyr Asn
485 490 495
Arg Arg Gly Asp Leu Ala Ile His Leu Val Ser Pro Met Gly Thr Arg
500 505 510
Ser Thr Leu Leu Ala Ala Arg Pro His Asp Tyr Ser Ala Asp Gly Phe
515 520 525
Asn Asp Trp Ala Phe Met Thr Thr His Ser Trp Asp Glu Asp Pro Ser
530 535 540
Gly Glu Trp Val Leu Glu Ile Glu Asn Thr Ser Glu Ala Asn Asn Tyr
545 550 555 560
Gly Thr Leu Thr Lys Phe Thr Leu Val Leu Tyr Gly Thr Ala Pro Glu
565 570 575
Gly Leu Pro Val Pro Pro Glu Ser Ser Gly Cys Lys Thr Leu Thr Ser
580 585 590
Ser Gln Ala Cys Val Val Cys Glu Glu Gly Phe Ser Leu His Gln Lys
595 600 605
Ser Cys Val Gln His Cys Pro Pro Gly Phe Ala Pro Gln Val Leu Asp
610 615 620
Thr His Tyr Ser Thr Glu Asn Asp Val Glu Thr Ile Arg Ala Ser Val
625 630 635 640
Cys Ala Pro Cys His Ala Ser Cys Ala Thr Cys Gln Gly Pro Ala Leu
645 650 655
Thr Asp Cys Leu Ser Cys Pro Ser His Ala Ser Leu Asp Pro Val Glu
660 665 670
Gln Thr Cys Ser Arg Gln Ser Gln Ser Ser Arg Glu Ser Pro Pro Gln
675 680 685
Gln Gln Pro Pro Arg Leu Pro Pro Glu Val Glu Ala Gly Gln Arg Leu
690 695 700
Arg Ala Gly Leu Leu Pro Ser His Leu Pro Glu Val Val Ala Gly Leu
705 710 715 720
Ser Cys Ala Phe Ile Val Leu Val Phe Val Thr Val Phe Leu Val Leu
725 730 735
Gln Leu Arg Ser Gly Phe Ser Phe Arg Gly Val Lys Val Tyr Thr Met
740 745 750
Asp Arg Gly Leu Ile Ser Tyr Lys Gly Leu Pro Pro Glu Ala Trp Gln
755 760 765
Glu Glu Cys Pro Ser Asp Ser Glu Glu Asp Glu Gly Arg Gly Glu Arg
770 775 780
Thr Ala Phe Ile Lys Asp Gln Ser Ala Leu
785 790
<210> 60
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 其他蛋白酶切割位点
<220>
<221> misc_feature
<222> (1)..(1)
<223> Xaa可以是任何天然产生的氨基酸
<220>
<221> misc_feature
<222> (3)..(5)
<223> Xaa可以是任何天然产生的氨基酸
<400> 60
Xaa Asp Xaa Xaa Xaa Leu Leu
1 5
<210> 61
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 其他蛋白酶切割位点
<220>
<221> misc_feature
<222> (1)..(1)
<223> Xaa可以是任何天然产生的氨基酸
<220>
<221> misc_feature
<222> (3)..(5)
<223> Xaa可以是任何天然产生的氨基酸
<400> 61
Xaa Glu Xaa Xaa Xaa Leu Leu
1 5
<210> 62
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 其他蛋白酶切割位点
<220>
<221> misc_feature
<222> (1)..(1)
<223> Xaa可以是任何天然产生的氨基酸
<220>
<221> misc_feature
<222> (3)..(5)
<223> Xaa可以是任何天然产生的氨基酸
<400> 62
Xaa Glu Xaa Xaa Xaa Ile Leu
1 5
<210> 63
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 其他蛋白酶切割位点
<220>
<221> misc_feature
<222> (1)..(1)
<223> Xaa可以是任何天然产生的氨基酸
<220>
<221> misc_feature
<222> (3)..(5)
<223> Xaa可以是任何天然产生的氨基酸
<400> 63
Xaa Glu Xaa Xaa Xaa Leu Met
1 5
<210> 64
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 其他蛋白酶切割位点
<220>
<221> misc_feature
<222> (2)..(3)
<223> Xaa可以是任何天然产生的氨基酸
<220>
<221> SITE
<222> (4)..(4)
<223> Xaa可以是任何疏水性氨基酸
<400> 64
Tyr Xaa Xaa Xaa
1
<210> 65
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> TEV切割位点
<400> 65
Glu Asn Leu Tyr Phe Gln Gly
1 5
<210> 66
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 凝血酶切割位点
<400> 66
Leu Val Pro Arg Gly Ser
1 5
<210> 67
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> PreScission切割位点
<400> 67
Leu Glu Val Leu Phe Gln Gly Pro
1 5
<210> 68
<211> 1296
<212> PRT
<213> 肉毒梭菌（Clostridium botulinum）
<400> 68
Met Pro Phe Val Asn Lys Gln Phe Asn Tyr Lys Asp Pro Val Asn Gly
1 5 10 15
Val Asp Ile Ala Tyr Ile Lys Ile Pro Asn Ala Gly Gln Met Gln Pro
20 25 30
Val Lys Ala Phe Lys Ile His Asn Lys Ile Trp Val Ile Pro Glu Arg
35 40 45
Asp Thr Phe Thr Asn Pro Glu Glu Gly Asp Leu Asn Pro Pro Pro Glu
50 55 60
Ala Lys Gln Val Pro Val Ser Tyr Tyr Asp Ser Thr Tyr Leu Ser Thr
65 70 75 80
Asp Asn Glu Lys Asp Asn Tyr Leu Lys Gly Val Thr Lys Leu Phe Glu
85 90 95
Arg Ile Tyr Ser Thr Asp Leu Gly Arg Met Leu Leu Thr Ser Ile Val
100 105 110
Arg Gly Ile Pro Phe Trp Gly Gly Ser Thr Ile Asp Thr Glu Leu Lys
115 120 125
Val Ile Asp Thr Asn Cys Ile Asn Val Ile Gln Pro Asp Gly Ser Tyr
130 135 140
Arg Ser Glu Glu Leu Asn Leu Val Ile Ile Gly Pro Ser Ala Asp Ile
145 150 155 160
Ile Gln Phe Glu Cys Lys Ser Phe Gly His Glu Val Leu Asn Leu Thr
165 170 175
Arg Asn Gly Tyr Gly Ser Thr Gln Tyr Ile Arg Phe Ser Pro Asp Phe
180 185 190
Thr Phe Gly Phe Glu Glu Ser Leu Glu Val Asp Thr Asn Pro Leu Leu
195 200 205
Gly Ala Gly Lys Phe Ala Thr Asp Pro Ala Val Thr Leu Ala His Glu
210 215 220
Leu Ile His Ala Gly His Arg Leu Tyr Gly Ile Ala Ile Asn Pro Asn
225 230 235 240
Arg Val Phe Lys Val Asn Thr Asn Ala Tyr Tyr Glu Met Ser Gly Leu
245 250 255
Glu Val Ser Phe Glu Glu Leu Arg Thr Phe Gly Gly His Asp Ala Lys
260 265 270
Phe Ile Asp Ser Leu Gln Glu Asn Glu Phe Arg Leu Tyr Tyr Tyr Asn
275 280 285
Lys Phe Lys Asp Ile Ala Ser Thr Leu Asn Lys Ala Lys Ser Ile Val
290 295 300
Gly Thr Thr Ala Ser Leu Gln Tyr Met Lys Asn Val Phe Lys Glu Lys
305 310 315 320
Tyr Leu Leu Ser Glu Asp Thr Ser Gly Lys Phe Ser Val Asp Lys Leu
325 330 335
Lys Phe Asp Lys Leu Tyr Lys Met Leu Thr Glu Ile Tyr Thr Glu Asp
340 345 350
Asn Phe Val Lys Phe Phe Lys Val Leu Asn Arg Lys Thr Tyr Leu Asn
355 360 365
Phe Asp Lys Ala Val Phe Lys Ile Asn Ile Val Pro Lys Val Asn Tyr
370 375 380
Thr Ile Tyr Asp Gly Phe Asn Leu Arg Asn Thr Asn Leu Ala Ala Asn
385 390 395 400
Phe Asn Gly Gln Asn Thr Glu Ile Asn Asn Met Asn Phe Thr Lys Leu
405 410 415
Lys Asn Phe Thr Gly Leu Phe Glu Phe Tyr Lys Leu Leu Cys Val Arg
420 425 430
Gly Ile Ile Thr Ser Lys Thr Lys Ser Leu Asp Lys Gly Tyr Asn Lys
435 440 445
Ala Leu Asn Asp Leu Cys Ile Lys Val Asn Asn Trp Asp Leu Phe Phe
450 455 460
Ser Pro Ser Glu Asp Asn Phe Thr Asn Asp Leu Asn Lys Gly Glu Glu
465 470 475 480
Ile Thr Ser Asp Thr Asn Ile Glu Ala Ala Glu Glu Asn Ile Ser Leu
485 490 495
Asp Leu Ile Gln Gln Tyr Tyr Leu Thr Phe Asn Phe Asp Asn Glu Pro
500 505 510
Glu Asn Ile Ser Ile Glu Asn Leu Ser Ser Asp Ile Ile Gly Gln Leu
515 520 525
Glu Leu Met Pro Asn Ile Glu Arg Phe Pro Asn Gly Lys Lys Tyr Glu
530 535 540
Leu Asp Lys Tyr Thr Met Phe His Tyr Leu Arg Ala Gln Glu Phe Glu
545 550 555 560
His Gly Lys Ser Arg Ile Ala Leu Thr Asn Ser Val Asn Glu Ala Leu
565 570 575
Leu Asn Pro Ser Arg Val Tyr Thr Phe Phe Ser Ser Asp Tyr Val Lys
580 585 590
Lys Val Asn Lys Ala Thr Glu Ala Ala Met Phe Leu Gly Trp Val Glu
595 600 605
Gln Leu Val Tyr Asp Phe Thr Asp Glu Thr Ser Glu Val Ser Thr Thr
610 615 620
Asp Lys Ile Ala Asp Ile Thr Ile Ile Ile Pro Tyr Ile Gly Pro Ala
625 630 635 640
Leu Asn Ile Gly Asn Met Leu Tyr Lys Asp Asp Phe Val Gly Ala Leu
645 650 655
Ile Phe Ser Gly Ala Val Ile Leu Leu Glu Phe Ile Pro Glu Ile Ala
660 665 670
Ile Pro Val Leu Gly Thr Phe Ala Leu Val Ser Tyr Ile Ala Asn Lys
675 680 685
Val Leu Thr Val Gln Thr Ile Asp Asn Ala Leu Ser Lys Arg Asn Glu
690 695 700
Lys Trp Asp Glu Val Tyr Lys Tyr Ile Val Thr Asn Trp Leu Ala Lys
705 710 715 720
Val Asn Thr Gln Ile Asp Leu Ile Arg Lys Lys Met Lys Glu Ala Leu
725 730 735
Glu Asn Gln Ala Glu Ala Thr Lys Ala Ile Ile Asn Tyr Gln Tyr Asn
740 745 750
Gln Tyr Thr Glu Glu Glu Lys Asn Asn Ile Asn Phe Asn Ile Asp Asp
755 760 765
Leu Ser Ser Lys Leu Asn Glu Ser Ile Asn Lys Ala Met Ile Asn Ile
770 775 780
Asn Lys Phe Leu Asn Gln Cys Ser Val Ser Tyr Leu Met Asn Ser Met
785 790 795 800
Ile Pro Tyr Gly Val Lys Arg Leu Glu Asp Phe Asp Ala Ser Leu Lys
805 810 815
Asp Ala Leu Leu Lys Tyr Ile Tyr Asp Asn Arg Gly Thr Leu Ile Gly
820 825 830
Gln Val Asp Arg Leu Lys Asp Lys Val Asn Asn Thr Leu Ser Thr Asp
835 840 845
Ile Pro Phe Gln Leu Ser Lys Tyr Val Asp Asn Gln Arg Leu Leu Ser
850 855 860
Thr Phe Thr Glu Tyr Ile Lys Asn Ile Ile Asn Thr Ser Ile Leu Asn
865 870 875 880
Leu Arg Tyr Glu Ser Asn His Leu Ile Asp Leu Ser Arg Tyr Ala Ser
885 890 895
Lys Ile Asn Ile Gly Ser Lys Val Asn Phe Asp Pro Ile Asp Lys Asn
900 905 910
Gln Ile Gln Leu Phe Asn Leu Glu Ser Ser Lys Ile Glu Val Ile Leu
915 920 925
Lys Asn Ala Ile Val Tyr Asn Ser Met Tyr Glu Asn Phe Ser Thr Ser
930 935 940
Phe Trp Ile Arg Ile Pro Lys Tyr Phe Asn Ser Ile Ser Leu Asn Asn
945 950 955 960
Glu Tyr Thr Ile Ile Asn Cys Met Glu Asn Asn Ser Gly Trp Lys Val
965 970 975
Ser Leu Asn Tyr Gly Glu Ile Ile Trp Thr Leu Gln Asp Thr Gln Glu
980 985 990
Ile Lys Gln Arg Val Val Phe Lys Tyr Ser Gln Met Ile Asn Ile Ser
995 1000 1005
Asp Tyr Ile Asn Arg Trp Ile Phe Val Thr Ile Thr Asn Asn Arg
1010 1015 1020
Leu Asn Asn Ser Lys Ile Tyr Ile Asn Gly Arg Leu Ile Asp Gln
1025 1030 1035
Lys Pro Ile Ser Asn Leu Gly Asn Ile His Ala Ser Asn Asn Ile
1040 1045 1050
Met Phe Lys Leu Asp Gly Cys Arg Asp Thr His Arg Tyr Ile Trp
1055 1060 1065
Ile Lys Tyr Phe Asn Leu Phe Asp Lys Glu Leu Asn Glu Lys Glu
1070 1075 1080
Ile Lys Asp Leu Tyr Asp Asn Gln Ser Asn Ser Gly Ile Leu Lys
1085 1090 1095
Asp Phe Trp Gly Asp Tyr Leu Gln Tyr Asp Lys Pro Tyr Tyr Met
1100 1105 1110
Leu Asn Leu Tyr Asp Pro Asn Lys Tyr Val Asp Val Asn Asn Val
1115 1120 1125
Gly Ile Arg Gly Tyr Met Tyr Leu Lys Gly Pro Arg Gly Ser Val
1130 1135 1140
Met Thr Thr Asn Ile Tyr Leu Asn Ser Ser Leu Tyr Arg Gly Thr
1145 1150 1155
Lys Phe Ile Ile Lys Lys Tyr Ala Ser Gly Asn Lys Asp Asn Ile
1160 1165 1170
Val Arg Asn Asn Asp Arg Val Tyr Ile Asn Val Val Val Lys Asn
1175 1180 1185
Lys Glu Tyr Arg Leu Ala Thr Asn Ala Ser Gln Ala Gly Val Glu
1190 1195 1200
Lys Ile Leu Ser Ala Leu Glu Ile Pro Asp Val Gly Asn Leu Ser
1205 1210 1215
Gln Val Val Val Met Lys Ser Lys Asn Asp Gln Gly Ile Thr Asn
1220 1225 1230
Lys Cys Lys Met Asn Leu Gln Asp Asn Asn Gly Asn Asp Ile Gly
1235 1240 1245
Phe Ile Gly Phe His Gln Phe Asn Asn Ile Ala Lys Leu Val Ala
1250 1255 1260
Ser Asn Trp Tyr Asn Arg Gln Ile Glu Arg Ser Ser Arg Thr Leu
1265 1270 1275
Gly Cys Ser Trp Glu Phe Ile Pro Val Asp Asp Gly Trp Gly Glu
1280 1285 1290
Arg Pro Leu
1295
<210> 69
<211> 1304
<212> PRT
<213> 人工序列
<220>
<223> 非工程化BoNT/AB嵌合体
<400> 69
Met Pro Phe Val Asn Lys Gln Phe Asn Tyr Lys Asp Pro Val Asn Gly
1 5 10 15
Val Asp Ile Ala Tyr Ile Lys Ile Pro Asn Ala Gly Gln Met Gln Pro
20 25 30
Val Lys Ala Phe Lys Ile His Asn Lys Ile Trp Val Ile Pro Glu Arg
35 40 45
Asp Thr Phe Thr Asn Pro Glu Glu Gly Asp Leu Asn Pro Pro Pro Glu
50 55 60
Ala Lys Gln Val Pro Val Ser Tyr Tyr Asp Ser Thr Tyr Leu Ser Thr
65 70 75 80
Asp Asn Glu Lys Asp Asn Tyr Leu Lys Gly Val Thr Lys Leu Phe Glu
85 90 95
Arg Ile Tyr Ser Thr Asp Leu Gly Arg Met Leu Leu Thr Ser Ile Val
100 105 110
Arg Gly Ile Pro Phe Trp Gly Gly Ser Thr Ile Asp Thr Glu Leu Lys
115 120 125
Val Ile Asp Thr Asn Cys Ile Asn Val Ile Gln Pro Asp Gly Ser Tyr
130 135 140
Arg Ser Glu Glu Leu Asn Leu Val Ile Ile Gly Pro Ser Ala Asp Ile
145 150 155 160
Ile Gln Phe Glu Cys Lys Ser Phe Gly His Glu Val Leu Asn Leu Thr
165 170 175
Arg Asn Gly Tyr Gly Ser Thr Gln Tyr Ile Arg Phe Ser Pro Asp Phe
180 185 190
Thr Phe Gly Phe Glu Glu Ser Leu Glu Val Asp Thr Asn Pro Leu Leu
195 200 205
Gly Ala Gly Lys Phe Ala Thr Asp Pro Ala Val Thr Leu Ala His Glu
210 215 220
Leu Ile His Ala Gly His Arg Leu Tyr Gly Ile Ala Ile Asn Pro Asn
225 230 235 240
Arg Val Phe Lys Val Asn Thr Asn Ala Tyr Tyr Glu Met Ser Gly Leu
245 250 255
Glu Val Ser Phe Glu Glu Leu Arg Thr Phe Gly Gly His Asp Ala Lys
260 265 270
Phe Ile Asp Ser Leu Gln Glu Asn Glu Phe Arg Leu Tyr Tyr Tyr Asn
275 280 285
Lys Phe Lys Asp Ile Ala Ser Thr Leu Asn Lys Ala Lys Ser Ile Val
290 295 300
Gly Thr Thr Ala Ser Leu Gln Tyr Met Lys Asn Val Phe Lys Glu Lys
305 310 315 320
Tyr Leu Leu Ser Glu Asp Thr Ser Gly Lys Phe Ser Val Asp Lys Leu
325 330 335
Lys Phe Asp Lys Leu Tyr Lys Met Leu Thr Glu Ile Tyr Thr Glu Asp
340 345 350
Asn Phe Val Lys Phe Phe Lys Val Leu Asn Arg Lys Thr Tyr Leu Asn
355 360 365
Phe Asp Lys Ala Val Phe Lys Ile Asn Ile Val Pro Lys Val Asn Tyr
370 375 380
Thr Ile Tyr Asp Gly Phe Asn Leu Arg Asn Thr Asn Leu Ala Ala Asn
385 390 395 400
Phe Asn Gly Gln Asn Thr Glu Ile Asn Asn Met Asn Phe Thr Lys Leu
405 410 415
Lys Asn Phe Thr Gly Leu Phe Glu Phe Tyr Lys Leu Leu Cys Val Arg
420 425 430
Gly Ile Ile Thr Ser Lys Thr Lys Ser Leu Asp Lys Gly Tyr Asn Lys
435 440 445
Ala Leu Asn Asp Leu Cys Ile Lys Val Asn Asn Trp Asp Leu Phe Phe
450 455 460
Ser Pro Ser Glu Asp Asn Phe Thr Asn Asp Leu Asn Lys Gly Glu Glu
465 470 475 480
Ile Thr Ser Asp Thr Asn Ile Glu Ala Ala Glu Glu Asn Ile Ser Leu
485 490 495
Asp Leu Ile Gln Gln Tyr Tyr Leu Thr Phe Asn Phe Asp Asn Glu Pro
500 505 510
Glu Asn Ile Ser Ile Glu Asn Leu Ser Ser Asp Ile Ile Gly Gln Leu
515 520 525
Glu Leu Met Pro Asn Ile Glu Arg Phe Pro Asn Gly Lys Lys Tyr Glu
530 535 540
Leu Asp Lys Tyr Thr Met Phe His Tyr Leu Arg Ala Gln Glu Phe Glu
545 550 555 560
His Gly Lys Ser Arg Ile Ala Leu Thr Asn Ser Val Asn Glu Ala Leu
565 570 575
Leu Asn Pro Ser Arg Val Tyr Thr Phe Phe Ser Ser Asp Tyr Val Lys
580 585 590
Lys Val Asn Lys Ala Thr Glu Ala Ala Met Phe Leu Gly Trp Val Glu
595 600 605
Gln Leu Val Tyr Asp Phe Thr Asp Glu Thr Ser Glu Val Ser Thr Thr
610 615 620
Asp Lys Ile Ala Asp Ile Thr Ile Ile Ile Pro Tyr Ile Gly Pro Ala
625 630 635 640
Leu Asn Ile Gly Asn Met Leu Tyr Lys Asp Asp Phe Val Gly Ala Leu
645 650 655
Ile Phe Ser Gly Ala Val Ile Leu Leu Glu Phe Ile Pro Glu Ile Ala
660 665 670
Ile Pro Val Leu Gly Thr Phe Ala Leu Val Ser Tyr Ile Ala Asn Lys
675 680 685
Val Leu Thr Val Gln Thr Ile Asp Asn Ala Leu Ser Lys Arg Asn Glu
690 695 700
Lys Trp Asp Glu Val Tyr Lys Tyr Ile Val Thr Asn Trp Leu Ala Lys
705 710 715 720
Val Asn Thr Gln Ile Asp Leu Ile Arg Lys Lys Met Lys Glu Ala Leu
725 730 735
Glu Asn Gln Ala Glu Ala Thr Lys Ala Ile Ile Asn Tyr Gln Tyr Asn
740 745 750
Gln Tyr Thr Glu Glu Glu Lys Asn Asn Ile Asn Phe Asn Ile Asp Asp
755 760 765
Leu Ser Ser Lys Leu Asn Glu Ser Ile Asn Lys Ala Met Ile Asn Ile
770 775 780
Asn Lys Phe Leu Asn Gln Cys Ser Val Ser Tyr Leu Met Asn Ser Met
785 790 795 800
Ile Pro Tyr Gly Val Lys Arg Leu Glu Asp Phe Asp Ala Ser Leu Lys
805 810 815
Asp Ala Leu Leu Lys Tyr Ile Tyr Asp Asn Arg Gly Thr Leu Ile Gly
820 825 830
Gln Val Asp Arg Leu Lys Asp Lys Val Asn Asn Thr Leu Ser Thr Asp
835 840 845
Ile Pro Phe Gln Leu Ser Lys Tyr Val Asp Asn Gln Arg Leu Leu Ser
850 855 860
Thr Phe Thr Glu Tyr Ile Lys Asn Ile Leu Asn Asn Ile Ile Leu Asn
865 870 875 880
Leu Arg Tyr Lys Asp Asn Asn Leu Ile Asp Leu Ser Gly Tyr Gly Ala
885 890 895
Lys Val Glu Val Tyr Asp Gly Val Glu Leu Asn Asp Lys Asn Gln Phe
900 905 910
Lys Leu Thr Ser Ser Ala Asn Ser Lys Ile Arg Val Thr Gln Asn Gln
915 920 925
Asn Ile Ile Phe Asn Ser Val Phe Leu Asp Phe Ser Val Ser Phe Trp
930 935 940
Ile Arg Ile Pro Lys Tyr Lys Asn Asp Gly Ile Gln Asn Tyr Ile His
945 950 955 960
Asn Glu Tyr Thr Ile Ile Asn Cys Met Lys Asn Asn Ser Gly Trp Lys
965 970 975
Ile Ser Ile Arg Gly Asn Arg Ile Ile Trp Thr Leu Ile Asp Ile Asn
980 985 990
Gly Lys Thr Lys Ser Val Phe Phe Glu Tyr Asn Ile Arg Glu Asp Ile
995 1000 1005
Ser Glu Tyr Ile Asn Arg Trp Phe Phe Val Thr Ile Thr Asn Asn
1010 1015 1020
Leu Asn Asn Ala Lys Ile Tyr Ile Asn Gly Lys Leu Glu Ser Asn
1025 1030 1035
Thr Asp Ile Lys Asp Ile Arg Glu Val Ile Ala Asn Gly Glu Ile
1040 1045 1050
Ile Phe Lys Leu Asp Gly Asp Ile Asp Arg Thr Gln Phe Ile Trp
1055 1060 1065
Met Lys Tyr Phe Ser Ile Phe Asn Thr Glu Leu Ser Gln Ser Asn
1070 1075 1080
Ile Glu Glu Arg Tyr Lys Ile Gln Ser Tyr Ser Glu Tyr Leu Lys
1085 1090 1095
Asp Phe Trp Gly Asn Pro Leu Met Tyr Asn Lys Glu Tyr Tyr Met
1100 1105 1110
Phe Asn Ala Gly Asn Lys Asn Ser Tyr Ile Lys Leu Lys Lys Asp
1115 1120 1125
Ser Pro Val Gly Glu Ile Leu Thr Arg Ser Lys Tyr Asn Gln Asn
1130 1135 1140
Ser Lys Tyr Ile Asn Tyr Arg Asp Leu Tyr Ile Gly Glu Lys Phe
1145 1150 1155
Ile Ile Arg Arg Lys Ser Asn Ser Gln Ser Ile Asn Asp Asp Ile
1160 1165 1170
Val Arg Lys Glu Asp Tyr Ile Tyr Leu Asp Phe Phe Asn Leu Asn
1175 1180 1185
Gln Glu Trp Arg Val Tyr Thr Tyr Lys Tyr Phe Lys Lys Glu Glu
1190 1195 1200
Met Lys Leu Phe Leu Ala Pro Ile Tyr Asp Ser Asp Glu Phe Tyr
1205 1210 1215
Asn Thr Ile Gln Ile Lys Glu Tyr Asp Glu Gln Pro Thr Tyr Ser
1220 1225 1230
Cys Gln Leu Leu Phe Lys Lys Asp Glu Glu Ser Thr Asp Glu Ile
1235 1240 1245
Gly Leu Ile Gly Ile His Arg Phe Tyr Glu Ser Gly Ile Val Phe
1250 1255 1260
Glu Glu Tyr Lys Asp Tyr Phe Cys Ile Ser Lys Trp Tyr Leu Lys
1265 1270 1275
Glu Val Lys Arg Lys Pro Tyr Asn Leu Lys Leu Gly Cys Asn Trp
1280 1285 1290
Gln Phe Ile Pro Lys Asp Glu Gly Trp Thr Glu
1295 1300
<210> 70
<211> 1304
<212> PRT
<213> 人工序列
<220>
<223> 工程化BoNT/AB嵌合体
<400> 70
Met Pro Phe Val Asn Lys Gln Phe Asn Tyr Lys Asp Pro Val Asn Gly
1 5 10 15
Val Asp Ile Ala Tyr Ile Lys Ile Pro Asn Ala Gly Gln Met Gln Pro
20 25 30
Val Lys Ala Phe Lys Ile His Asn Lys Ile Trp Val Ile Pro Glu Arg
35 40 45
Asp Thr Phe Thr Asn Pro Glu Glu Gly Asp Leu Asn Pro Pro Pro Glu
50 55 60
Ala Lys Gln Val Pro Val Ser Tyr Tyr Asp Ser Thr Tyr Leu Ser Thr
65 70 75 80
Asp Asn Glu Lys Asp Asn Tyr Leu Lys Gly Val Thr Lys Leu Phe Glu
85 90 95
Arg Ile Tyr Ser Thr Asp Leu Gly Arg Met Leu Leu Thr Ser Ile Val
100 105 110
Arg Gly Ile Pro Phe Trp Gly Gly Ser Thr Ile Asp Thr Glu Leu Lys
115 120 125
Val Ile Asp Thr Asn Cys Ile Asn Val Ile Gln Pro Asp Gly Ser Tyr
130 135 140
Arg Ser Glu Glu Leu Asn Leu Val Ile Ile Gly Pro Ser Ala Asp Ile
145 150 155 160
Ile Gln Phe Glu Cys Lys Ser Phe Gly His Glu Val Leu Asn Leu Thr
165 170 175
Arg Asn Gly Tyr Gly Ser Thr Gln Tyr Ile Arg Phe Ser Pro Asp Phe
180 185 190
Thr Phe Gly Phe Glu Glu Ser Leu Glu Val Asp Thr Asn Pro Leu Leu
195 200 205
Gly Ala Gly Lys Phe Ala Thr Asp Pro Ala Val Thr Leu Ala His Glu
210 215 220
Leu Ile His Ala Gly His Arg Leu Tyr Gly Ile Ala Ile Asn Pro Asn
225 230 235 240
Arg Val Phe Lys Val Asn Thr Asn Ala Tyr Tyr Glu Met Ser Gly Leu
245 250 255
Glu Val Ser Phe Glu Glu Leu Arg Thr Phe Gly Gly His Asp Ala Lys
260 265 270
Phe Ile Asp Ser Leu Gln Glu Asn Glu Phe Arg Leu Tyr Tyr Tyr Asn
275 280 285
Lys Phe Lys Asp Ile Ala Ser Thr Leu Asn Lys Ala Lys Ser Ile Val
290 295 300
Gly Thr Thr Ala Ser Leu Gln Tyr Met Lys Asn Val Phe Lys Glu Lys
305 310 315 320
Tyr Leu Leu Ser Glu Asp Thr Ser Gly Lys Phe Ser Val Asp Lys Leu
325 330 335
Lys Phe Asp Lys Leu Tyr Lys Met Leu Thr Glu Ile Tyr Thr Glu Asp
340 345 350
Asn Phe Val Lys Phe Phe Lys Val Leu Asn Arg Lys Thr Tyr Leu Asn
355 360 365
Phe Asp Lys Ala Val Phe Lys Ile Asn Ile Val Pro Lys Val Asn Tyr
370 375 380
Thr Ile Tyr Asp Gly Phe Asn Leu Arg Asn Thr Asn Leu Ala Ala Asn
385 390 395 400
Phe Asn Gly Gln Asn Thr Glu Ile Asn Asn Met Asn Phe Thr Lys Leu
405 410 415
Lys Asn Phe Thr Gly Leu Phe Glu Phe Tyr Lys Leu Leu Cys Val Arg
420 425 430
Gly Ile Lys Gln Lys Ser Ser Asn Ser Arg Lys Lys Arg Ser Thr Ser
435 440 445
Ala Leu Asn Asp Leu Cys Ile Lys Val Asn Asn Trp Asp Leu Phe Phe
450 455 460
Ser Pro Ser Glu Asp Asn Phe Thr Asn Asp Leu Asn Lys Gly Glu Glu
465 470 475 480
Ile Thr Ser Asp Thr Asn Ile Glu Ala Ala Glu Glu Asn Ile Ser Leu
485 490 495
Asp Leu Ile Gln Gln Tyr Tyr Leu Thr Phe Asn Phe Asp Asn Glu Pro
500 505 510
Glu Asn Ile Ser Ile Glu Asn Leu Ser Ser Asp Ile Ile Gly Gln Leu
515 520 525
Glu Leu Met Pro Asn Ile Glu Arg Phe Pro Asn Gly Lys Lys Tyr Glu
530 535 540
Leu Asp Lys Tyr Thr Met Phe His Tyr Leu Arg Ala Gln Glu Phe Glu
545 550 555 560
His Gly Lys Ser Arg Ile Ala Leu Thr Asn Ser Val Asn Glu Ala Leu
565 570 575
Leu Asn Pro Ser Arg Val Tyr Thr Phe Phe Ser Ser Asp Tyr Val Lys
580 585 590
Lys Val Asn Lys Ala Thr Glu Ala Ala Met Phe Leu Gly Trp Val Glu
595 600 605
Gln Leu Val Tyr Asp Phe Thr Asp Glu Thr Ser Glu Val Ser Thr Thr
610 615 620
Asp Lys Ile Ala Asp Ile Thr Ile Ile Ile Pro Tyr Ile Gly Pro Ala
625 630 635 640
Leu Asn Ile Gly Asn Met Leu Tyr Lys Asp Asp Phe Val Gly Ala Leu
645 650 655
Ile Phe Ser Gly Ala Val Ile Leu Leu Glu Phe Ile Pro Glu Ile Ala
660 665 670
Ile Pro Val Leu Gly Thr Phe Ala Leu Val Ser Tyr Ile Ala Asn Lys
675 680 685
Val Leu Thr Val Gln Thr Ile Asp Asn Ala Leu Ser Lys Arg Asn Glu
690 695 700
Lys Trp Asp Glu Val Tyr Lys Tyr Ile Val Thr Asn Trp Leu Ala Lys
705 710 715 720
Val Asn Thr Gln Ile Asp Leu Ile Arg Lys Lys Met Lys Glu Ala Leu
725 730 735
Glu Asn Gln Ala Glu Ala Thr Lys Ala Ile Ile Asn Tyr Gln Tyr Asn
740 745 750
Gln Tyr Thr Glu Glu Glu Lys Asn Asn Ile Asn Phe Asn Ile Asp Asp
755 760 765
Leu Ser Ser Lys Leu Asn Glu Ser Ile Asn Lys Ala Met Ile Asn Ile
770 775 780
Asn Lys Phe Leu Asn Gln Cys Ser Val Ser Tyr Leu Met Asn Ser Met
785 790 795 800
Ile Pro Tyr Gly Val Lys Arg Leu Glu Asp Phe Asp Ala Ser Leu Lys
805 810 815
Asp Ala Leu Leu Lys Tyr Ile Tyr Asp Asn Arg Gly Thr Leu Ile Gly
820 825 830
Gln Val Asp Arg Leu Lys Asp Lys Val Asn Asn Thr Leu Ser Thr Asp
835 840 845
Ile Pro Phe Gln Leu Ser Lys Tyr Val Asp Asn Gln Arg Leu Leu Ser
850 855 860
Thr Phe Thr Glu Tyr Ile Lys Asn Ile Leu Asn Asn Ile Ile Leu Asn
865 870 875 880
Leu Arg Tyr Lys Asp Asn Asn Leu Ile Asp Leu Ser Gly Tyr Gly Ala
885 890 895
Lys Val Glu Val Tyr Asp Gly Val Glu Leu Asn Asp Lys Asn Gln Phe
900 905 910
Lys Leu Thr Ser Ser Ala Asn Ser Lys Ile Arg Val Thr Gln Asn Gln
915 920 925
Asn Ile Ile Phe Asn Ser Val Phe Leu Asp Phe Ser Val Ser Phe Trp
930 935 940
Ile Arg Ile Pro Lys Tyr Lys Asn Asp Gly Ile Gln Asn Tyr Ile His
945 950 955 960
Asn Glu Tyr Thr Ile Ile Asn Cys Met Lys Asn Asn Ser Gly Trp Lys
965 970 975
Ile Ser Ile Arg Gly Asn Arg Ile Ile Trp Thr Leu Ile Asp Ile Asn
980 985 990
Gly Lys Thr Lys Ser Val Phe Phe Glu Tyr Asn Ile Arg Glu Asp Ile
995 1000 1005
Ser Glu Tyr Ile Asn Arg Trp Phe Phe Val Thr Ile Thr Asn Asn
1010 1015 1020
Leu Asn Asn Ala Lys Ile Tyr Ile Asn Gly Lys Leu Glu Ser Asn
1025 1030 1035
Thr Asp Ile Lys Asp Ile Arg Glu Val Ile Ala Asn Gly Glu Ile
1040 1045 1050
Ile Phe Lys Leu Asp Gly Asp Ile Asp Arg Thr Gln Phe Ile Trp
1055 1060 1065
Met Lys Tyr Phe Ser Ile Phe Asn Thr Glu Leu Ser Gln Ser Asn
1070 1075 1080
Ile Glu Glu Arg Tyr Lys Ile Gln Ser Tyr Ser Glu Tyr Leu Lys
1085 1090 1095
Asp Phe Trp Gly Asn Pro Leu Met Tyr Asn Lys Glu Tyr Tyr Met
1100 1105 1110
Phe Asn Ala Gly Asn Lys Asn Ser Tyr Ile Lys Leu Lys Lys Asp
1115 1120 1125
Ser Pro Val Gly Glu Ile Leu Thr Arg Ser Lys Tyr Asn Gln Asn
1130 1135 1140
Ser Lys Tyr Ile Asn Tyr Arg Asp Leu Tyr Ile Gly Glu Lys Phe
1145 1150 1155
Ile Ile Arg Arg Lys Ser Asn Ser Gln Ser Ile Asn Asp Asp Ile
1160 1165 1170
Val Arg Lys Glu Asp Tyr Ile Tyr Leu Asp Phe Phe Asn Leu Asn
1175 1180 1185
Gln Glu Trp Arg Val Tyr Thr Tyr Lys Tyr Phe Lys Lys Glu Glu
1190 1195 1200
Met Lys Leu Phe Leu Ala Pro Ile Tyr Asp Ser Asp Glu Phe Tyr
1205 1210 1215
Asn Thr Ile Gln Ile Lys Glu Tyr Asp Glu Gln Pro Thr Tyr Ser
1220 1225 1230
Cys Gln Leu Leu Phe Lys Lys Asp Glu Glu Ser Thr Asp Glu Ile
1235 1240 1245
Gly Leu Ile Gly Ile His Arg Phe Tyr Glu Ser Gly Ile Val Phe
1250 1255 1260
Glu Glu Tyr Lys Asp Tyr Phe Cys Ile Ser Lys Trp Tyr Leu Lys
1265 1270 1275
Glu Val Lys Arg Lys Pro Tyr Asn Leu Lys Leu Gly Cys Asn Trp
1280 1285 1290
Gln Phe Ile Pro Lys Asp Glu Gly Trp Thr Glu
1295 1300
<210> 71
<211> 1302
<212> PRT
<213> 人工序列
<220>
<223> 工程化BoNT/B
<400> 71
Met Pro Val Thr Ile Asn Asn Phe Asn Tyr Asn Asp Pro Ile Asp Asn
1 5 10 15
Asn Asn Ile Ile Met Met Glu Pro Pro Phe Ala Arg Gly Thr Gly Arg
20 25 30
Tyr Tyr Lys Ala Phe Lys Ile Thr Asp Arg Ile Trp Ile Ile Pro Glu
35 40 45
Arg Tyr Thr Phe Gly Tyr Lys Pro Glu Asp Phe Asn Lys Ser Ser Gly
50 55 60
Ile Phe Asn Arg Asp Val Cys Glu Tyr Tyr Asp Pro Asp Tyr Leu Asn
65 70 75 80
Thr Asn Asp Lys Lys Asn Ile Phe Leu Gln Thr Met Ile Lys Leu Phe
85 90 95
Asn Arg Ile Lys Ser Lys Pro Leu Gly Glu Lys Leu Leu Glu Met Ile
100 105 110
Ile Asn Gly Ile Pro Tyr Leu Gly Asp Arg Arg Val Pro Leu Glu Glu
115 120 125
Phe Asn Thr Asn Ile Ala Ser Val Thr Val Asn Lys Leu Ile Ser Asn
130 135 140
Pro Gly Glu Val Glu Arg Lys Lys Gly Ile Phe Ala Asn Leu Ile Ile
145 150 155 160
Phe Gly Pro Gly Pro Val Leu Asn Glu Asn Glu Thr Ile Asp Ile Gly
165 170 175
Ile Gln Asn His Phe Ala Ser Arg Glu Gly Phe Gly Gly Ile Met Gln
180 185 190
Met Lys Phe Cys Pro Glu Tyr Val Ser Val Phe Asn Asn Val Gln Glu
195 200 205
Asn Lys Gly Ala Ser Ile Phe Asn Arg Arg Gly Tyr Phe Ser Asp Pro
210 215 220
Ala Leu Ile Leu Met His Glu Leu Ile His Val Leu His Gly Leu Tyr
225 230 235 240
Gly Ile Lys Val Asp Asp Leu Pro Ile Val Pro Asn Glu Lys Lys Phe
245 250 255
Phe Met Gln Ser Thr Asp Ala Ile Gln Ala Glu Glu Leu Tyr Thr Phe
260 265 270
Gly Gly Gln Asp Pro Ser Ile Ile Thr Pro Ser Thr Asp Lys Ser Ile
275 280 285
Tyr Asp Lys Val Leu Gln Asn Phe Arg Gly Ile Val Asp Arg Leu Asn
290 295 300
Lys Val Leu Val Cys Ile Ser Asp Pro Asn Ile Asn Ile Asn Ile Tyr
305 310 315 320
Lys Asn Lys Phe Lys Asp Lys Tyr Lys Phe Val Glu Asp Ser Glu Gly
325 330 335
Lys Tyr Ser Ile Asp Val Glu Ser Phe Asp Lys Leu Tyr Lys Ser Leu
340 345 350
Met Phe Gly Phe Thr Glu Thr Asn Ile Ala Glu Asn Tyr Lys Ile Lys
355 360 365
Thr Arg Ala Ser Tyr Phe Ser Asp Ser Leu Pro Pro Val Lys Ile Lys
370 375 380
Asn Leu Leu Asp Asn Glu Ile Tyr Thr Ile Glu Glu Gly Phe Asn Ile
385 390 395 400
Ser Asp Lys Asp Met Glu Lys Glu Tyr Arg Gly Gln Asn Lys Ala Ile
405 410 415
Asn Lys Gln Ala Tyr Glu Glu Ile Ser Lys Glu His Leu Ala Val Tyr
420 425 430
Lys Ile Gln Met Cys Lys Ser Val Lys Gln Lys Ser Ser Asn Ser Arg
435 440 445
Lys Lys Arg Ser Thr Ser Gly Ile Cys Ile Asp Val Asp Asn Glu Asp
450 455 460
Leu Phe Phe Ile Ala Asp Lys Asn Ser Phe Ser Asp Asp Leu Ser Lys
465 470 475 480
Asn Glu Arg Ile Glu Tyr Asn Thr Gln Ser Asn Tyr Ile Glu Asn Asp
485 490 495
Phe Pro Ile Asn Glu Leu Ile Leu Asp Thr Asp Leu Ile Ser Lys Ile
500 505 510
Glu Leu Pro Ser Glu Asn Thr Glu Ser Leu Thr Asp Phe Asn Val Asp
515 520 525
Val Pro Val Tyr Glu Lys Gln Pro Ala Ile Lys Lys Ile Phe Thr Asp
530 535 540
Glu Asn Thr Ile Phe Gln Tyr Leu Tyr Ser Gln Thr Phe Pro Leu Asp
545 550 555 560
Ile Arg Asp Ile Ser Leu Thr Ser Ser Phe Asp Asp Ala Leu Leu Phe
565 570 575
Ser Asn Lys Val Tyr Ser Phe Phe Ser Met Asp Tyr Ile Lys Thr Ala
580 585 590
Asn Lys Val Val Glu Ala Gly Leu Phe Ala Gly Trp Val Lys Gln Ile
595 600 605
Val Asn Asp Phe Val Ile Glu Ala Asn Lys Ser Asn Thr Met Asp Lys
610 615 620
Ile Ala Asp Ile Ser Leu Ile Val Pro Tyr Ile Gly Leu Ala Leu Asn
625 630 635 640
Val Gly Asn Glu Thr Ala Lys Gly Asn Phe Glu Asn Ala Phe Glu Ile
645 650 655
Ala Gly Ala Ser Ile Leu Leu Glu Phe Ile Pro Glu Leu Leu Ile Pro
660 665 670
Val Val Gly Ala Phe Leu Leu Glu Ser Tyr Ile Asp Asn Lys Asn Lys
675 680 685
Ile Ile Lys Thr Ile Asp Asn Ala Leu Thr Lys Arg Asn Glu Lys Trp
690 695 700
Ser Asp Met Tyr Gly Leu Ile Val Ala Gln Trp Leu Ser Thr Val Asn
705 710 715 720
Thr Gln Phe Tyr Thr Ile Lys Glu Gly Met Tyr Lys Ala Leu Asn Tyr
725 730 735
Gln Ala Gln Ala Leu Glu Glu Ile Ile Lys Tyr Arg Tyr Asn Ile Tyr
740 745 750
Ser Glu Lys Glu Lys Ser Asn Ile Asn Ile Asp Phe Asn Asp Ile Asn
755 760 765
Ser Lys Leu Asn Glu Gly Ile Asn Gln Ala Ile Asp Asn Ile Asn Asn
770 775 780
Phe Ile Asn Gly Cys Ser Val Ser Tyr Leu Met Lys Lys Met Ile Pro
785 790 795 800
Leu Ala Val Glu Lys Leu Leu Asp Phe Asp Asn Thr Leu Lys Lys Asn
805 810 815
Leu Leu Asn Tyr Ile Asp Glu Asn Lys Leu Tyr Leu Ile Gly Ser Ala
820 825 830
Glu Tyr Glu Lys Ser Lys Val Asn Lys Tyr Leu Lys Thr Ile Met Pro
835 840 845
Phe Asp Leu Ser Ile Tyr Thr Asn Asp Thr Ile Leu Ile Glu Met Phe
850 855 860
Asn Lys Tyr Asn Ser Glu Ile Leu Asn Asn Ile Ile Leu Asn Leu Arg
865 870 875 880
Tyr Lys Asp Asn Asn Leu Ile Asp Leu Ser Gly Tyr Gly Ala Lys Val
885 890 895
Glu Val Tyr Asp Gly Val Glu Leu Asn Asp Lys Asn Gln Phe Lys Leu
900 905 910
Thr Ser Ser Ala Asn Ser Lys Ile Arg Val Thr Gln Asn Gln Asn Ile
915 920 925
Ile Phe Asn Ser Val Phe Leu Asp Phe Ser Val Ser Phe Trp Ile Arg
930 935 940
Ile Pro Lys Tyr Lys Asn Asp Gly Ile Gln Asn Tyr Ile His Asn Glu
945 950 955 960
Tyr Thr Ile Ile Asn Cys Met Lys Asn Asn Ser Gly Trp Lys Ile Ser
965 970 975
Ile Arg Gly Asn Arg Ile Ile Trp Thr Leu Ile Asp Ile Asn Gly Lys
980 985 990
Thr Lys Ser Val Phe Phe Glu Tyr Asn Ile Arg Glu Asp Ile Ser Glu
995 1000 1005
Tyr Ile Asn Arg Trp Phe Phe Val Thr Ile Thr Asn Asn Leu Asn
1010 1015 1020
Asn Ala Lys Ile Tyr Ile Asn Gly Lys Leu Glu Ser Asn Thr Asp
1025 1030 1035
Ile Lys Asp Ile Arg Glu Val Ile Ala Asn Gly Glu Ile Ile Phe
1040 1045 1050
Lys Leu Asp Gly Asp Ile Asp Arg Thr Gln Phe Ile Trp Met Lys
1055 1060 1065
Tyr Phe Ser Ile Phe Asn Thr Glu Leu Ser Gln Ser Asn Ile Glu
1070 1075 1080
Glu Arg Tyr Lys Ile Gln Ser Tyr Ser Glu Tyr Leu Lys Asp Phe
1085 1090 1095
Trp Gly Asn Pro Leu Met Tyr Asn Lys Glu Tyr Tyr Met Phe Asn
1100 1105 1110
Ala Gly Asn Lys Asn Ser Tyr Ile Lys Leu Lys Lys Asp Ser Pro
1115 1120 1125
Val Gly Glu Ile Leu Thr Arg Ser Lys Tyr Asn Gln Asn Ser Lys
1130 1135 1140
Tyr Ile Asn Tyr Arg Asp Leu Tyr Ile Gly Glu Lys Phe Ile Ile
1145 1150 1155
Arg Arg Lys Ser Asn Ser Gln Ser Ile Asn Asp Asp Ile Val Arg
1160 1165 1170
Lys Glu Asp Tyr Ile Tyr Leu Asp Phe Phe Asn Leu Asn Gln Glu
1175 1180 1185
Trp Arg Val Tyr Thr Tyr Lys Tyr Phe Lys Lys Glu Glu Glu Lys
1190 1195 1200
Leu Phe Leu Ala Pro Ile Ser Asp Ser Asp Glu Phe Tyr Asn Thr
1205 1210 1215
Ile Gln Ile Lys Glu Tyr Asp Glu Gln Pro Thr Tyr Ser Cys Gln
1220 1225 1230
Leu Leu Phe Lys Lys Asp Glu Glu Ser Thr Asp Glu Ile Gly Leu
1235 1240 1245
Ile Gly Ile His Arg Phe Tyr Glu Ser Gly Ile Val Phe Glu Glu
1250 1255 1260
Tyr Lys Asp Tyr Phe Cys Ile Ser Lys Trp Tyr Leu Lys Glu Val
1265 1270 1275
Lys Arg Lys Pro Tyr Asn Leu Lys Leu Gly Cys Asn Trp Gln Phe
1280 1285 1290
Ile Pro Lys Asp Glu Gly Trp Thr Glu
1295 1300
<210> 72
<211> 1297
<212> PRT
<213> 人工序列
<220>
<223> 工程化BoNT/C
<400> 72
Met Pro Ile Thr Ile Asn Asn Phe Asn Tyr Ser Asp Pro Val Asp Asn
1 5 10 15
Lys Asn Ile Leu Tyr Leu Asp Thr His Leu Asn Thr Leu Ala Asn Glu
20 25 30
Pro Glu Lys Ala Phe Arg Ile Thr Gly Asn Ile Trp Val Ile Pro Asp
35 40 45
Arg Phe Ser Arg Asn Ser Asn Pro Asn Leu Asn Lys Pro Pro Arg Val
50 55 60
Thr Ser Pro Lys Ser Gly Tyr Tyr Asp Pro Asn Tyr Leu Ser Thr Asp
65 70 75 80
Ser Asp Lys Asp Pro Phe Leu Lys Glu Ile Ile Lys Leu Phe Lys Arg
85 90 95
Ile Asn Ser Arg Glu Ile Gly Glu Glu Leu Ile Tyr Arg Leu Ser Thr
100 105 110
Asp Ile Pro Phe Pro Gly Asn Asn Asn Thr Pro Ile Asn Thr Phe Asp
115 120 125
Phe Asp Val Asp Phe Asn Ser Val Asp Val Lys Thr Arg Gln Gly Asn
130 135 140
Asn Trp Val Lys Thr Gly Ser Ile Asn Pro Ser Val Ile Ile Thr Gly
145 150 155 160
Pro Arg Glu Asn Ile Ile Asp Pro Glu Thr Ser Thr Phe Lys Leu Thr
165 170 175
Asn Asn Thr Phe Ala Ala Gln Glu Gly Phe Gly Ala Leu Ser Ile Ile
180 185 190
Ser Ile Ser Pro Arg Phe Met Leu Thr Tyr Ser Asn Ala Thr Asn Asp
195 200 205
Val Gly Glu Gly Arg Phe Ser Lys Ser Glu Phe Cys Met Asp Pro Ile
210 215 220
Leu Ile Leu Met His Glu Leu Asn His Ala Met His Asn Leu Tyr Gly
225 230 235 240
Ile Ala Ile Pro Asn Asp Gln Thr Ile Ser Ser Val Thr Ser Asn Ile
245 250 255
Phe Tyr Ser Gln Tyr Asn Val Lys Leu Glu Tyr Ala Glu Ile Tyr Ala
260 265 270
Phe Gly Gly Pro Thr Ile Asp Leu Ile Pro Lys Ser Ala Arg Lys Tyr
275 280 285
Phe Glu Glu Lys Ala Leu Asp Tyr Tyr Arg Ser Ile Ala Lys Arg Leu
290 295 300
Asn Ser Ile Thr Thr Ala Asn Pro Ser Ser Phe Asn Lys Tyr Ile Gly
305 310 315 320
Glu Tyr Lys Gln Lys Leu Ile Arg Lys Tyr Arg Phe Val Val Glu Ser
325 330 335
Ser Gly Glu Val Thr Val Asn Arg Asn Lys Phe Val Glu Leu Tyr Asn
340 345 350
Glu Leu Thr Gln Ile Phe Thr Glu Phe Asn Tyr Ala Lys Ile Tyr Asn
355 360 365
Val Gln Asn Arg Lys Ile Tyr Leu Ser Asn Val Tyr Thr Pro Val Thr
370 375 380
Ala Asn Ile Leu Asp Asp Asn Val Tyr Asp Ile Gln Asn Gly Phe Asn
385 390 395 400
Ile Pro Lys Ser Asn Leu Asn Val Leu Phe Met Gly Gln Asn Leu Ser
405 410 415
Arg Asn Pro Ala Leu Arg Lys Val Asn Pro Glu Asn Met Leu Tyr Leu
420 425 430
Phe Thr Lys Phe Cys His Lys Ala Ile Lys Gln Lys Ser Ser Asn Ser
435 440 445
Arg Lys Lys Arg Ser Thr Ser Thr Leu Asp Cys Arg Glu Leu Leu Val
450 455 460
Lys Asn Thr Asp Leu Pro Phe Ile Gly Asp Ile Ser Asp Val Lys Thr
465 470 475 480
Asp Ile Phe Leu Arg Lys Asp Ile Asn Glu Glu Thr Glu Val Ile Tyr
485 490 495
Tyr Pro Asp Asn Val Ser Val Asp Gln Val Ile Leu Ser Lys Asn Thr
500 505 510
Ser Glu His Gly Gln Leu Asp Leu Leu Tyr Pro Ser Ile Asp Ser Glu
515 520 525
Ser Glu Ile Leu Pro Gly Glu Asn Gln Val Phe Tyr Asp Asn Arg Thr
530 535 540
Gln Asn Val Asp Tyr Leu Asn Ser Tyr Tyr Tyr Leu Glu Ser Gln Lys
545 550 555 560
Leu Ser Asp Asn Val Glu Asp Phe Thr Phe Thr Arg Ser Ile Glu Glu
565 570 575
Ala Leu Asp Asn Ser Ala Lys Val Tyr Thr Tyr Phe Pro Thr Leu Ala
580 585 590
Asn Lys Val Asn Ala Gly Val Gln Gly Gly Leu Phe Leu Met Trp Ala
595 600 605
Asn Asp Val Val Glu Asp Phe Thr Thr Asn Ile Leu Arg Lys Asp Thr
610 615 620
Leu Asp Lys Ile Ser Asp Val Ser Ala Ile Ile Pro Tyr Ile Gly Pro
625 630 635 640
Ala Leu Asn Ile Ser Asn Ser Val Arg Arg Gly Asn Phe Thr Glu Ala
645 650 655
Phe Ala Val Thr Gly Val Thr Ile Leu Leu Glu Ala Phe Pro Glu Phe
660 665 670
Thr Ile Pro Ala Leu Gly Ala Phe Val Ile Tyr Ser Lys Val Gln Glu
675 680 685
Arg Asn Glu Ile Ile Lys Thr Ile Asp Asn Cys Leu Glu Gln Arg Ile
690 695 700
Lys Arg Trp Lys Asp Ser Tyr Glu Trp Met Met Gly Thr Trp Leu Ser
705 710 715 720
Arg Ile Ile Thr Gln Phe Asn Asn Ile Ser Tyr Gln Met Tyr Asp Ser
725 730 735
Leu Asn Tyr Gln Ala Gly Ala Ile Lys Ala Lys Ile Asp Leu Glu Tyr
740 745 750
Lys Lys Tyr Ser Gly Ser Asp Lys Glu Asn Ile Lys Ser Gln Val Glu
755 760 765
Asn Leu Lys Asn Ser Leu Asp Val Lys Ile Ser Glu Ala Met Asn Asn
770 775 780
Ile Asn Lys Phe Ile Arg Glu Cys Ser Val Thr Tyr Leu Phe Lys Asn
785 790 795 800
Met Leu Pro Lys Val Ile Asp Glu Leu Asn Glu Phe Asp Arg Asn Thr
805 810 815
Lys Ala Lys Leu Ile Asn Leu Ile Asp Ser His Asn Ile Ile Leu Val
820 825 830
Gly Glu Val Asp Lys Leu Lys Ala Lys Val Asn Asn Ser Phe Gln Asn
835 840 845
Thr Ile Pro Phe Asn Ile Phe Ser Tyr Thr Asn Asn Ser Leu Leu Lys
850 855 860
Asp Ile Ile Asn Glu Tyr Phe Asn Asn Ile Asn Asp Ser Lys Ile Leu
865 870 875 880
Ser Leu Gln Asn Arg Lys Asn Thr Leu Val Asp Thr Ser Gly Tyr Asn
885 890 895
Ala Glu Val Ser Glu Glu Gly Asp Val Gln Leu Asn Pro Ile Phe Pro
900 905 910
Phe Asp Phe Lys Leu Gly Ser Ser Gly Glu Asp Arg Gly Lys Val Ile
915 920 925
Val Thr Gln Asn Glu Asn Ile Val Tyr Asn Ser Met Tyr Glu Ser Phe
930 935 940
Ser Ile Ser Phe Trp Ile Arg Ile Asn Lys Trp Val Ser Asn Leu Pro
945 950 955 960
Gly Tyr Thr Ile Ile Asp Ser Val Lys Asn Asn Ser Gly Trp Ser Ile
965 970 975
Gly Ile Ile Ser Asn Phe Leu Val Phe Thr Leu Lys Gln Asn Glu Asp
980 985 990
Ser Glu Gln Ser Ile Asn Phe Ser Tyr Asp Ile Ser Asn Asn Ala Pro
995 1000 1005
Gly Tyr Asn Lys Trp Phe Phe Val Thr Val Thr Asn Asn Met Met
1010 1015 1020
Gly Asn Met Lys Ile Tyr Ile Asn Gly Lys Leu Ile Asp Thr Ile
1025 1030 1035
Lys Val Lys Glu Leu Thr Gly Ile Asn Phe Ser Lys Thr Ile Thr
1040 1045 1050
Phe Glu Ile Asn Lys Ile Pro Asp Thr Gly Leu Ile Thr Ser Asp
1055 1060 1065
Ser Asp Asn Ile Asn Met Trp Ile Arg Asp Phe Tyr Ile Phe Ala
1070 1075 1080
Lys Glu Leu Asp Gly Lys Asp Ile Asn Ile Leu Phe Asn Ser Leu
1085 1090 1095
Gln Tyr Thr Asn Val Val Lys Asp Tyr Trp Gly Asn Asp Leu Arg
1100 1105 1110
Tyr Asn Lys Glu Tyr Tyr Met Val Asn Ile Asp Tyr Leu Asn Arg
1115 1120 1125
Tyr Met Tyr Ala Asn Ser Arg Gln Ile Val Phe Asn Thr Arg Arg
1130 1135 1140
Asn Asn Asn Asp Phe Asn Glu Gly Tyr Lys Ile Ile Ile Lys Arg
1145 1150 1155
Ile Arg Gly Asn Thr Asn Asp Thr Arg Val Arg Gly Gly Asp Ile
1160 1165 1170
Leu Tyr Phe Asp Met Thr Ile Asn Asn Lys Ala Tyr Asn Leu Phe
1175 1180 1185
Met Lys Asn Glu Thr Met Tyr Ala Asp Asn His Ser Thr Glu Asp
1190 1195 1200
Ile Tyr Ala Ile Gly Leu Arg Glu Gln Thr Lys Asp Ile Asn Asp
1205 1210 1215
Asn Ile Ile Phe Gln Ile Gln Pro Met Asn Asn Thr Tyr Tyr Tyr
1220 1225 1230
Ala Ser Gln Ile Phe Lys Ser Asn Phe Asn Gly Glu Asn Ile Ser
1235 1240 1245
Gly Ile Cys Ser Ile Gly Thr Tyr Arg Phe Arg Leu Gly Gly Asp
1250 1255 1260
Trp Tyr Arg His Asn Tyr Leu Val Pro Thr Val Lys Gln Gly Asn
1265 1270 1275
Tyr Ala Ser Leu Leu Glu Ser Thr Ser Thr His Trp Gly Phe Val
1280 1285 1290
Pro Val Ser Glu
1295
<210> 73
<211> 1284
<212> PRT
<213> 人工序列
<220>
<223> 工程化BoNT/D
<400> 73
Met Thr Trp Pro Val Lys Asp Phe Asn Tyr Ser Asp Pro Val Asn Asp
1 5 10 15
Asn Asp Ile Leu Tyr Leu Arg Ile Pro Gln Asn Lys Leu Ile Thr Thr
20 25 30
Pro Val Lys Ala Phe Met Ile Thr Gln Asn Ile Trp Val Ile Pro Glu
35 40 45
Arg Phe Ser Ser Asp Thr Asn Pro Ser Leu Ser Lys Pro Pro Arg Pro
50 55 60
Thr Ser Lys Tyr Gln Ser Tyr Tyr Asp Pro Ser Tyr Leu Ser Thr Asp
65 70 75 80
Glu Gln Lys Asp Thr Phe Leu Lys Gly Ile Ile Lys Leu Phe Lys Arg
85 90 95
Ile Asn Glu Arg Asp Ile Gly Lys Lys Leu Ile Asn Tyr Leu Val Val
100 105 110
Gly Ser Pro Phe Met Gly Asp Ser Ser Thr Pro Glu Asp Thr Phe Asp
115 120 125
Phe Thr Arg His Thr Thr Asn Ile Ala Val Glu Lys Phe Glu Asn Gly
130 135 140
Ser Trp Lys Val Thr Asn Ile Ile Thr Pro Ser Val Leu Ile Phe Gly
145 150 155 160
Pro Leu Pro Asn Ile Leu Asp Tyr Thr Ala Ser Leu Thr Leu Gln Gly
165 170 175
Gln Gln Ser Asn Pro Ser Phe Glu Gly Phe Gly Thr Leu Ser Ile Leu
180 185 190
Lys Val Ala Pro Glu Phe Leu Leu Thr Phe Ser Asp Val Thr Ser Asn
195 200 205
Gln Ser Ser Ala Val Leu Gly Lys Ser Ile Phe Cys Met Asp Pro Val
210 215 220
Ile Ala Leu Met His Glu Leu Thr His Ser Leu His Gln Leu Tyr Gly
225 230 235 240
Ile Asn Ile Pro Ser Asp Lys Arg Ile Arg Pro Gln Val Ser Glu Gly
245 250 255
Phe Phe Ser Gln Asp Gly Pro Asn Val Gln Phe Glu Glu Leu Tyr Thr
260 265 270
Phe Gly Gly Leu Asp Val Glu Ile Ile Pro Gln Ile Glu Arg Ser Gln
275 280 285
Leu Arg Glu Lys Ala Leu Gly His Tyr Lys Asp Ile Ala Lys Arg Leu
290 295 300
Asn Asn Ile Asn Lys Thr Ile Pro Ser Ser Trp Ile Ser Asn Ile Asp
305 310 315 320
Lys Tyr Lys Lys Ile Phe Ser Glu Lys Tyr Asn Phe Asp Lys Asp Asn
325 330 335
Thr Gly Asn Phe Val Val Asn Ile Asp Lys Phe Asn Ser Leu Tyr Ser
340 345 350
Asp Leu Thr Asn Val Met Ser Glu Val Val Tyr Ser Ser Gln Tyr Asn
355 360 365
Val Lys Asn Arg Thr His Tyr Phe Ser Arg His Tyr Leu Pro Val Phe
370 375 380
Ala Asn Ile Leu Asp Asp Asn Ile Tyr Thr Ile Arg Asp Gly Phe Asn
385 390 395 400
Leu Thr Asn Lys Gly Phe Asn Ile Glu Asn Ser Gly Gln Asn Ile Glu
405 410 415
Arg Asn Pro Ala Leu Gln Lys Leu Ser Ser Glu Ser Val Val Asp Leu
420 425 430
Phe Thr Lys Val Cys Leu Arg Leu Lys Gln Lys Ser Ser Asn Ser Arg
435 440 445
Lys Lys Arg Ser Thr Ser Asp Ser Thr Cys Ile Lys Val Lys Asn Asn
450 455 460
Arg Leu Pro Tyr Val Ala Asp Lys Asp Ser Ile Ser Gln Glu Ile Phe
465 470 475 480
Glu Asn Lys Ile Ile Thr Asp Glu Thr Asn Val Gln Asn Tyr Ser Asp
485 490 495
Lys Phe Ser Leu Asp Glu Ser Ile Leu Asp Gly Gln Val Pro Ile Asn
500 505 510
Pro Glu Ile Val Asp Pro Leu Leu Pro Asn Val Asn Met Glu Pro Leu
515 520 525
Asn Leu Pro Gly Glu Glu Ile Val Phe Tyr Asp Asp Ile Thr Lys Tyr
530 535 540
Val Asp Tyr Leu Asn Ser Tyr Tyr Tyr Leu Glu Ser Gln Lys Leu Ser
545 550 555 560
Asn Asn Val Glu Asn Ile Thr Leu Thr Thr Ser Val Glu Glu Ala Leu
565 570 575
Gly Tyr Ser Asn Lys Ile Tyr Thr Phe Leu Pro Ser Leu Ala Glu Lys
580 585 590
Val Asn Lys Gly Val Gln Ala Gly Leu Phe Leu Asn Trp Ala Asn Glu
595 600 605
Val Val Glu Asp Phe Thr Thr Asn Ile Met Lys Lys Asp Thr Leu Asp
610 615 620
Lys Ile Ser Asp Val Ser Val Ile Ile Pro Tyr Ile Gly Pro Ala Leu
625 630 635 640
Asn Ile Gly Asn Ser Ala Leu Arg Gly Asn Phe Asn Gln Ala Phe Ala
645 650 655
Thr Ala Gly Val Ala Phe Leu Leu Glu Gly Phe Pro Glu Phe Thr Ile
660 665 670
Pro Ala Leu Gly Val Phe Thr Phe Tyr Ser Ser Ile Gln Glu Arg Glu
675 680 685
Lys Ile Ile Lys Thr Ile Glu Asn Cys Leu Glu Gln Arg Val Lys Arg
690 695 700
Trp Lys Asp Ser Tyr Gln Trp Met Val Ser Asn Trp Leu Ser Arg Ile
705 710 715 720
Thr Thr Gln Phe Asn His Ile Asn Tyr Gln Met Tyr Asp Ser Leu Ser
725 730 735
Tyr Gln Ala Asp Ala Ile Lys Ala Lys Ile Asp Leu Glu Tyr Lys Lys
740 745 750
Tyr Ser Gly Ser Asp Lys Glu Asn Ile Lys Ser Gln Val Glu Asn Leu
755 760 765
Lys Asn Ser Leu Asp Val Lys Ile Ser Glu Ala Met Asn Asn Ile Asn
770 775 780
Lys Phe Ile Arg Glu Cys Ser Val Thr Tyr Leu Phe Lys Asn Met Leu
785 790 795 800
Pro Lys Val Ile Asp Glu Leu Asn Lys Phe Asp Leu Arg Thr Lys Thr
805 810 815
Glu Leu Ile Asn Leu Ile Asp Ser His Asn Ile Ile Leu Val Gly Glu
820 825 830
Val Asp Arg Leu Lys Ala Lys Val Asn Glu Ser Phe Glu Asn Thr Met
835 840 845
Pro Phe Asn Ile Phe Ser Tyr Thr Asn Asn Ser Leu Leu Lys Asp Ile
850 855 860
Ile Asn Glu Tyr Phe Asn Ser Ile Asn Asp Ser Lys Ile Leu Ser Leu
865 870 875 880
Gln Asn Lys Lys Asn Ala Leu Val Asp Thr Ser Gly Tyr Asn Ala Glu
885 890 895
Val Arg Val Gly Asp Asn Val Gln Leu Asn Thr Ile Tyr Thr Asn Asp
900 905 910
Phe Lys Leu Ser Ser Ser Gly Asp Lys Ile Ile Val Asn Leu Asn Asn
915 920 925
Asn Ile Leu Tyr Ser Ala Ile Tyr Glu Asn Ser Ser Val Ser Phe Trp
930 935 940
Ile Lys Ile Ser Lys Asp Leu Thr Asn Ser His Asn Glu Tyr Thr Ile
945 950 955 960
Ile Asn Ser Ile Glu Gln Asn Ser Gly Trp Lys Leu Cys Ile Arg Asn
965 970 975
Gly Asn Ile Glu Trp Ile Leu Gln Asp Val Asn Arg Lys Tyr Lys Ser
980 985 990
Leu Ile Phe Asp Tyr Ser Glu Ser Leu Ser His Thr Gly Tyr Thr Asn
995 1000 1005
Lys Trp Phe Phe Val Thr Ile Thr Asn Asn Ile Met Gly Tyr Met
1010 1015 1020
Lys Leu Tyr Ile Asn Gly Glu Leu Lys Gln Ser Gln Lys Ile Glu
1025 1030 1035
Asp Leu Asp Glu Val Lys Leu Asp Lys Thr Ile Val Phe Gly Ile
1040 1045 1050
Asp Glu Asn Ile Asp Glu Asn Gln Met Leu Trp Ile Arg Asp Phe
1055 1060 1065
Asn Ile Phe Ser Lys Glu Leu Ser Asn Glu Asp Ile Asn Ile Val
1070 1075 1080
Tyr Glu Gly Gln Ile Leu Arg Asn Val Ile Lys Asp Tyr Trp Gly
1085 1090 1095
Asn Pro Leu Lys Phe Asp Thr Glu Tyr Tyr Ile Ile Asn Asp Asn
1100 1105 1110
Tyr Ile Asp Arg Tyr Ile Ala Pro Glu Ser Asn Val Leu Val Leu
1115 1120 1125
Val Gln Tyr Pro Asp Arg Ser Lys Leu Tyr Thr Gly Asn Pro Ile
1130 1135 1140
Thr Ile Lys Ser Val Ser Asp Lys Asn Pro Tyr Ser Arg Ile Leu
1145 1150 1155
Asn Gly Asp Asn Ile Ile Leu His Met Leu Tyr Asn Ser Arg Lys
1160 1165 1170
Tyr Met Ile Ile Arg Asp Thr Asp Thr Ile Tyr Ala Thr Gln Gly
1175 1180 1185
Gly Glu Cys Ser Gln Asn Cys Val Tyr Ala Leu Lys Leu Gln Ser
1190 1195 1200
Asn Leu Gly Asn Tyr Gly Ile Gly Ile Phe Ser Ile Lys Asn Ile
1205 1210 1215
Val Ser Lys Asn Lys Tyr Cys Ser Gln Ile Phe Ser Ser Phe Arg
1220 1225 1230
Glu Asn Thr Met Leu Leu Ala Asp Ile Tyr Lys Pro Trp Arg Phe
1235 1240 1245
Ser Phe Lys Asn Ala Tyr Thr Pro Val Ala Val Thr Asn Tyr Glu
1250 1255 1260
Thr Lys Leu Leu Ser Thr Ser Ser Phe Trp Lys Phe Ile Ser Arg
1265 1270 1275
Asp Pro Gly Trp Val Glu
1280
<210> 74
<211> 1257
<212> PRT
<213> 人工序列
<220>
<223> 工程化BoNT/E
<400> 74
Met Pro Lys Ile Asn Ser Phe Asn Tyr Asn Asp Pro Val Asn Asp Arg
1 5 10 15
Thr Ile Leu Tyr Ile Lys Pro Gly Gly Cys Gln Glu Phe Tyr Lys Ser
20 25 30
Phe Asn Ile Met Lys Asn Ile Trp Ile Ile Pro Glu Arg Asn Val Ile
35 40 45
Gly Thr Thr Pro Gln Asp Phe His Pro Pro Thr Ser Leu Lys Asn Gly
50 55 60
Asp Ser Ser Tyr Tyr Asp Pro Asn Tyr Leu Gln Ser Asp Glu Glu Lys
65 70 75 80
Asp Arg Phe Leu Lys Ile Val Thr Lys Ile Phe Asn Arg Ile Asn Asn
85 90 95
Asn Leu Ser Gly Gly Ile Leu Leu Glu Glu Leu Ser Lys Ala Asn Pro
100 105 110
Tyr Leu Gly Asn Asp Asn Thr Pro Asp Asn Gln Phe His Ile Gly Asp
115 120 125
Ala Ser Ala Val Glu Ile Lys Phe Ser Asn Gly Ser Gln Asp Ile Leu
130 135 140
Leu Pro Asn Val Ile Ile Met Gly Ala Glu Pro Asp Leu Phe Glu Thr
145 150 155 160
Asn Ser Ser Asn Ile Ser Leu Arg Asn Asn Tyr Met Pro Ser Asn His
165 170 175
Arg Phe Gly Ser Ile Ala Ile Val Thr Phe Ser Pro Glu Tyr Ser Phe
180 185 190
Arg Phe Asn Asp Asn Cys Met Asn Glu Phe Ile Gln Asp Pro Ala Leu
195 200 205
Thr Leu Met His Glu Leu Ile His Ser Leu His Gly Leu Tyr Gly Ala
210 215 220
Lys Gly Ile Thr Thr Lys Tyr Thr Ile Thr Gln Lys Gln Asn Pro Leu
225 230 235 240
Ile Thr Asn Ile Arg Gly Thr Asn Ile Glu Glu Phe Leu Thr Phe Gly
245 250 255
Gly Thr Asp Leu Asn Ile Ile Thr Ser Ala Gln Ser Asn Asp Ile Tyr
260 265 270
Thr Asn Leu Leu Ala Asp Tyr Lys Lys Ile Ala Ser Lys Leu Ser Lys
275 280 285
Val Gln Val Ser Asn Pro Leu Leu Asn Pro Tyr Lys Asp Val Phe Glu
290 295 300
Ala Lys Tyr Gly Leu Asp Lys Asp Ala Ser Gly Ile Tyr Ser Val Asn
305 310 315 320
Ile Asn Lys Phe Asn Asp Ile Phe Lys Lys Leu Tyr Ser Phe Thr Glu
325 330 335
Phe Asp Leu Arg Thr Lys Phe Gln Val Lys Cys Arg Gln Thr Tyr Ile
340 345 350
Gly Gln Tyr Lys Tyr Phe Lys Leu Ser Asn Leu Leu Asn Asp Ser Ile
355 360 365
Tyr Asn Ile Ser Glu Gly Tyr Asn Ile Asn Asn Leu Lys Val Asn Phe
370 375 380
Arg Gly Gln Asn Ala Asn Leu Asn Pro Arg Ile Ile Thr Pro Ile Thr
385 390 395 400
Gly Arg Gly Leu Val Lys Lys Ile Ile Arg Phe Cys Lys Asn Ile Lys
405 410 415
Gln Lys Ser Ser Asn Ser Arg Lys Lys Arg Ser Thr Ser Ser Ile Cys
420 425 430
Ile Glu Ile Asn Asn Gly Glu Leu Phe Phe Val Ala Ser Glu Asn Ser
435 440 445
Tyr Asn Asp Asp Asn Ile Asn Thr Pro Lys Glu Ile Asp Asp Thr Val
450 455 460
Thr Ser Asn Asn Asn Tyr Glu Asn Asp Leu Asp Gln Val Ile Leu Asn
465 470 475 480
Phe Asn Ser Glu Ser Ala Pro Gly Leu Ser Asp Glu Lys Leu Asn Leu
485 490 495
Thr Ile Gln Asn Asp Ala Tyr Ile Pro Lys Tyr Asp Ser Asn Gly Thr
500 505 510
Ser Asp Ile Glu Gln His Asp Val Asn Glu Leu Asn Val Phe Phe Tyr
515 520 525
Leu Asp Ala Gln Lys Val Pro Glu Gly Glu Asn Asn Val Asn Leu Thr
530 535 540
Ser Ser Ile Asp Thr Ala Leu Leu Glu Gln Pro Lys Ile Tyr Thr Phe
545 550 555 560
Phe Ser Ser Glu Phe Ile Asn Asn Val Asn Lys Pro Val Gln Ala Ala
565 570 575
Leu Phe Val Ser Trp Ile Gln Gln Val Leu Val Asp Phe Thr Thr Glu
580 585 590
Ala Asn Gln Lys Ser Thr Val Asp Lys Ile Ala Asp Ile Ser Ile Val
595 600 605
Val Pro Tyr Ile Gly Leu Ala Leu Asn Ile Gly Asn Glu Ala Gln Lys
610 615 620
Gly Asn Phe Lys Asp Ala Leu Glu Leu Leu Gly Ala Gly Ile Leu Leu
625 630 635 640
Glu Phe Glu Pro Glu Leu Leu Ile Pro Thr Ile Leu Val Phe Thr Ile
645 650 655
Lys Ser Phe Leu Gly Ser Ser Asp Asn Lys Asn Lys Val Ile Lys Ala
660 665 670
Ile Asn Asn Ala Leu Lys Glu Arg Asp Glu Lys Trp Lys Glu Val Tyr
675 680 685
Ser Phe Ile Val Ser Asn Trp Met Thr Lys Ile Asn Thr Gln Phe Asn
690 695 700
Lys Arg Lys Glu Gln Met Tyr Gln Ala Leu Gln Asn Gln Val Asn Ala
705 710 715 720
Ile Lys Thr Ile Ile Glu Ser Lys Tyr Asn Ser Tyr Thr Leu Glu Glu
725 730 735
Lys Asn Glu Leu Thr Asn Lys Tyr Asp Ile Lys Gln Ile Glu Asn Glu
740 745 750
Leu Asn Gln Lys Val Ser Ile Ala Met Asn Asn Ile Asp Arg Phe Leu
755 760 765
Thr Glu Ser Ser Ile Ser Tyr Leu Met Lys Ile Ile Asn Glu Val Lys
770 775 780
Ile Asn Lys Leu Arg Glu Tyr Asp Glu Asn Val Lys Thr Tyr Leu Leu
785 790 795 800
Asn Tyr Ile Ile Gln His Gly Ser Ile Leu Gly Glu Ser Gln Gln Glu
805 810 815
Leu Asn Ser Met Val Thr Asp Thr Leu Asn Asn Ser Ile Pro Phe Lys
820 825 830
Leu Ser Ser Tyr Thr Asp Asp Lys Ile Leu Ile Ser Tyr Phe Asn Lys
835 840 845
Phe Phe Lys Arg Ile Lys Ser Ser Ser Val Leu Asn Met Arg Tyr Lys
850 855 860
Asn Asp Lys Tyr Val Asp Thr Ser Gly Tyr Asp Ser Asn Ile Asn Ile
865 870 875 880
Asn Gly Asp Val Tyr Lys Tyr Pro Thr Asn Lys Asn Gln Phe Gly Ile
885 890 895
Tyr Asn Asp Lys Leu Ser Glu Val Asn Ile Ser Gln Asn Asp Tyr Ile
900 905 910
Ile Tyr Asp Asn Lys Tyr Lys Asn Phe Ser Ile Ser Phe Trp Val Arg
915 920 925
Ile Pro Asn Tyr Asp Asn Lys Ile Val Asn Val Asn Asn Glu Tyr Thr
930 935 940
Ile Ile Asn Cys Met Arg Asp Asn Asn Ser Gly Trp Lys Val Ser Leu
945 950 955 960
Asn His Asn Glu Ile Ile Trp Thr Phe Glu Asp Asn Arg Gly Ile Asn
965 970 975
Gln Lys Leu Ala Phe Asn Tyr Gly Asn Ala Asn Gly Ile Ser Asp Tyr
980 985 990
Ile Asn Lys Trp Ile Phe Val Thr Ile Thr Asn Asp Arg Leu Gly Asp
995 1000 1005
Ser Lys Leu Tyr Ile Asn Gly Asn Leu Ile Asp Gln Lys Ser Ile
1010 1015 1020
Leu Asn Leu Gly Asn Ile His Val Ser Asp Asn Ile Leu Phe Lys
1025 1030 1035
Ile Val Asn Cys Ser Tyr Thr Arg Tyr Ile Gly Ile Arg Tyr Phe
1040 1045 1050
Asn Ile Phe Asp Lys Glu Leu Asp Glu Thr Glu Ile Gln Thr Leu
1055 1060 1065
Tyr Ser Asn Glu Pro Asn Thr Asn Ile Leu Lys Asp Phe Trp Gly
1070 1075 1080
Asn Tyr Leu Leu Tyr Asp Lys Glu Tyr Tyr Leu Leu Asn Val Leu
1085 1090 1095
Lys Pro Asn Asn Phe Ile Asp Arg Arg Lys Asp Ser Thr Leu Ser
1100 1105 1110
Ile Asn Asn Ile Arg Ser Thr Ile Leu Leu Ala Asn Arg Leu Tyr
1115 1120 1125
Ser Gly Ile Lys Val Lys Ile Gln Arg Val Asn Asn Ser Ser Thr
1130 1135 1140
Asn Asp Asn Leu Val Arg Lys Asn Asp Gln Val Tyr Ile Asn Phe
1145 1150 1155
Val Ala Ser Lys Thr His Leu Phe Pro Leu Tyr Ala Asp Thr Ala
1160 1165 1170
Thr Thr Asn Lys Glu Lys Thr Ile Lys Ile Ser Ser Ser Gly Asn
1175 1180 1185
Arg Phe Asn Gln Val Val Val Met Asn Ser Val Gly Asn Cys Thr
1190 1195 1200
Met Asn Phe Lys Asn Asn Asn Gly Asn Asn Ile Gly Leu Leu Gly
1205 1210 1215
Phe Lys Ala Asp Thr Val Val Ala Ser Thr Trp Tyr Tyr Thr His
1220 1225 1230
Met Arg Asp His Thr Asn Ser Asn Gly Cys Phe Trp Asn Phe Ile
1235 1240 1245
Ser Glu Glu His Gly Trp Gln Glu Lys
1250 1255
<210> 75
<211> 1283
<212> PRT
<213> 人工序列
<220>
<223> 工程化BoNT/F
<400> 75
Met Pro Val Val Ile Asn Ser Phe Asn Tyr Asn Asp Pro Val Asn Asp
1 5 10 15
Asp Thr Ile Leu Tyr Met Gln Ile Pro Tyr Glu Glu Lys Ser Lys Lys
20 25 30
Tyr Tyr Lys Ala Phe Glu Ile Met Arg Asn Val Trp Ile Ile Pro Glu
35 40 45
Arg Asn Thr Ile Gly Thr Asp Pro Ser Asp Phe Asp Pro Pro Ala Ser
50 55 60
Leu Glu Asn Gly Ser Ser Ala Tyr Tyr Asp Pro Asn Tyr Leu Thr Thr
65 70 75 80
Asp Ala Glu Lys Asp Arg Tyr Leu Lys Thr Thr Ile Lys Leu Phe Lys
85 90 95
Arg Ile Asn Ser Asn Pro Ala Gly Glu Val Leu Leu Gln Glu Ile Ser
100 105 110
Tyr Ala Lys Pro Tyr Leu Gly Asn Glu His Thr Pro Ile Asn Glu Phe
115 120 125
His Pro Val Thr Arg Thr Thr Ser Val Asn Ile Lys Ser Ser Thr Asn
130 135 140
Val Lys Ser Ser Ile Ile Leu Asn Leu Leu Val Leu Gly Ala Gly Pro
145 150 155 160
Asp Ile Phe Glu Asn Ser Ser Tyr Pro Val Arg Lys Leu Met Asp Ser
165 170 175
Gly Gly Val Tyr Asp Pro Ser Asn Asp Gly Phe Gly Ser Ile Asn Ile
180 185 190
Val Thr Phe Ser Pro Glu Tyr Glu Tyr Thr Phe Asn Asp Ile Ser Gly
195 200 205
Gly Tyr Asn Ser Ser Thr Glu Ser Phe Ile Ala Asp Pro Ala Ile Ser
210 215 220
Leu Ala His Glu Leu Ile His Ala Leu His Gly Leu Tyr Gly Ala Arg
225 230 235 240
Gly Val Thr Tyr Lys Glu Thr Ile Lys Val Lys Gln Ala Pro Leu Met
245 250 255
Ile Ala Glu Lys Pro Ile Arg Leu Glu Glu Phe Leu Thr Phe Gly Gly
260 265 270
Gln Asp Leu Asn Ile Ile Thr Ser Ala Met Lys Glu Lys Ile Tyr Asn
275 280 285
Asn Leu Leu Ala Asn Tyr Glu Lys Ile Ala Thr Arg Leu Ser Arg Val
290 295 300
Asn Ser Ala Pro Pro Glu Tyr Asp Ile Asn Glu Tyr Lys Asp Tyr Phe
305 310 315 320
Gln Trp Lys Tyr Gly Leu Asp Lys Asn Ala Asp Gly Ser Tyr Thr Val
325 330 335
Asn Glu Asn Lys Phe Asn Glu Ile Tyr Lys Lys Leu Tyr Ser Phe Thr
340 345 350
Glu Ile Asp Leu Ala Asn Lys Phe Lys Val Lys Cys Arg Asn Thr Tyr
355 360 365
Phe Ile Lys Tyr Gly Phe Leu Lys Val Pro Asn Leu Leu Asp Asp Asp
370 375 380
Ile Tyr Thr Val Ser Glu Gly Phe Asn Ile Gly Asn Leu Ala Val Asn
385 390 395 400
Asn Arg Gly Gln Asn Ile Lys Leu Asn Pro Lys Ile Ile Asp Ser Ile
405 410 415
Pro Asp Lys Gly Leu Val Glu Lys Ile Val Lys Phe Cys Lys Ser Val
420 425 430
Ile Lys Gln Lys Ser Ser Asn Ser Arg Lys Lys Arg Ser Thr Ser Arg
435 440 445
Leu Cys Ile Arg Val Asn Asn Arg Glu Leu Phe Phe Val Ala Ser Glu
450 455 460
Ser Ser Tyr Asn Glu Asn Asp Ile Asn Thr Pro Lys Glu Ile Asp Asp
465 470 475 480
Thr Thr Asn Leu Asn Asn Asn Tyr Arg Asn Asn Leu Asp Glu Val Ile
485 490 495
Leu Asp Tyr Asn Ser Glu Thr Ile Pro Gln Ile Ser Asn Gln Thr Leu
500 505 510
Asn Thr Leu Val Gln Asp Asp Ser Tyr Val Pro Arg Tyr Asp Ser Asn
515 520 525
Gly Thr Ser Glu Ile Glu Glu His Asn Val Val Asp Leu Asn Val Phe
530 535 540
Phe Tyr Leu His Ala Gln Lys Val Pro Glu Gly Glu Thr Asn Ile Ser
545 550 555 560
Leu Thr Ser Ser Ile Asp Thr Ala Leu Ser Glu Glu Ser Gln Val Tyr
565 570 575
Thr Phe Phe Ser Ser Glu Phe Ile Asn Thr Ile Asn Lys Pro Val His
580 585 590
Ala Ala Leu Phe Ile Ser Trp Ile Asn Gln Val Ile Arg Asp Phe Thr
595 600 605
Thr Glu Ala Thr Gln Lys Ser Thr Phe Asp Lys Ile Ala Asp Ile Ser
610 615 620
Leu Val Val Pro Tyr Val Gly Leu Ala Leu Asn Ile Gly Asn Glu Val
625 630 635 640
Gln Lys Glu Asn Phe Lys Glu Ala Phe Glu Leu Leu Gly Ala Gly Ile
645 650 655
Leu Leu Glu Phe Val Pro Glu Leu Leu Ile Pro Thr Ile Leu Val Phe
660 665 670
Thr Ile Lys Ser Phe Ile Gly Ser Ser Glu Asn Lys Asn Lys Ile Ile
675 680 685
Lys Ala Ile Asn Asn Ser Leu Met Glu Arg Glu Thr Lys Trp Lys Glu
690 695 700
Ile Tyr Ser Trp Ile Val Ser Asn Trp Leu Thr Arg Ile Asn Thr Gln
705 710 715 720
Phe Asn Lys Arg Lys Glu Gln Met Tyr Gln Ala Leu Gln Asn Gln Val
725 730 735
Asp Ala Ile Lys Thr Val Ile Glu Tyr Lys Tyr Asn Asn Tyr Thr Ser
740 745 750
Asp Glu Arg Asn Arg Leu Glu Ser Glu Tyr Asn Ile Asn Asn Ile Arg
755 760 765
Glu Glu Leu Asn Lys Lys Val Ser Leu Ala Met Glu Asn Ile Glu Arg
770 775 780
Phe Ile Thr Glu Ser Ser Ile Phe Tyr Leu Met Lys Leu Ile Asn Glu
785 790 795 800
Ala Lys Val Ser Lys Leu Arg Glu Tyr Asp Glu Gly Val Lys Glu Tyr
805 810 815
Leu Leu Asp Tyr Ile Ser Glu His Arg Ser Ile Leu Gly Asn Ser Val
820 825 830
Gln Glu Leu Asn Asp Leu Val Thr Ser Thr Leu Asn Asn Ser Ile Pro
835 840 845
Phe Glu Leu Ser Ser Tyr Thr Asn Asp Lys Ile Leu Ile Leu Tyr Phe
850 855 860
Asn Lys Leu Tyr Lys Lys Ile Lys Asp Asn Ser Ile Leu Asp Met Arg
865 870 875 880
Tyr Glu Asn Asn Lys Phe Ile Asp Ile Ser Gly Tyr Gly Ser Asn Ile
885 890 895
Ser Ile Asn Gly Asp Val Tyr Ile Tyr Ser Thr Asn Arg Asn Gln Phe
900 905 910
Gly Ile Tyr Ser Ser Lys Pro Ser Glu Val Asn Ile Ala Gln Asn Asn
915 920 925
Asp Ile Ile Tyr Asn Gly Arg Tyr Gln Asn Phe Ser Ile Ser Phe Trp
930 935 940
Val Arg Ile Pro Lys Tyr Phe Asn Lys Val Asn Leu Asn Asn Glu Tyr
945 950 955 960
Thr Ile Ile Asp Cys Ile Arg Asn Asn Asn Ser Gly Trp Lys Ile Ser
965 970 975
Leu Asn Tyr Asn Lys Ile Ile Trp Thr Leu Gln Asp Thr Ala Gly Asn
980 985 990
Asn Gln Lys Leu Val Phe Asn Tyr Thr Gln Met Ile Ser Ile Ser Asp
995 1000 1005
Tyr Ile Asn Lys Trp Ile Phe Val Thr Ile Thr Asn Asn Arg Leu
1010 1015 1020
Gly Asn Ser Arg Ile Tyr Ile Asn Gly Asn Leu Ile Asp Glu Lys
1025 1030 1035
Ser Ile Ser Asn Leu Gly Asp Ile His Val Ser Asp Asn Ile Leu
1040 1045 1050
Phe Lys Ile Val Gly Cys Asn Asp Thr Arg Tyr Val Gly Ile Arg
1055 1060 1065
Tyr Phe Lys Val Phe Asp Thr Glu Leu Gly Lys Thr Glu Ile Glu
1070 1075 1080
Thr Leu Tyr Ser Asp Glu Pro Asp Pro Ser Ile Leu Lys Asp Phe
1085 1090 1095
Trp Gly Asn Tyr Leu Leu Tyr Asn Lys Arg Tyr Tyr Leu Leu Asn
1100 1105 1110
Leu Leu Arg Thr Asp Lys Ser Ile Thr Gln Asn Ser Asn Phe Leu
1115 1120 1125
Asn Ile Asn Gln Gln Arg Gly Val Tyr Gln Lys Pro Asn Ile Phe
1130 1135 1140
Ser Asn Thr Arg Leu Tyr Thr Gly Val Glu Val Ile Ile Arg Lys
1145 1150 1155
Asn Gly Ser Thr Asp Ile Ser Asn Thr Asp Asn Phe Val Arg Lys
1160 1165 1170
Asn Asp Leu Ala Tyr Ile Asn Val Val Asp Arg Asp Val Glu Tyr
1175 1180 1185
Arg Leu Tyr Ala Asp Ile Ser Ile Ala Lys Pro Glu Lys Ile Ile
1190 1195 1200
Lys Leu Ile Arg Thr Ser Asn Ser Asn Asn Ser Leu Gly Gln Ile
1205 1210 1215
Ile Val Met Asp Ser Ile Gly Asn Asn Cys Thr Met Asn Phe Gln
1220 1225 1230
Asn Asn Asn Gly Gly Asn Ile Gly Leu Leu Gly Phe His Ser Asn
1235 1240 1245
Asn Leu Val Ala Ser Ser Trp Tyr Tyr Asn Asn Ile Arg Lys Asn
1250 1255 1260
Thr Ser Ser Asn Gly Cys Phe Trp Ser Phe Ile Ser Lys Glu His
1265 1270 1275
Gly Trp Gln Glu Asn
1280
<210> 76
<211> 1304
<212> PRT
<213> 人工序列
<220>
<223> 工程化BoNT/G
<220>
<221> misc_feature
<222> (7)..(7)
<223> Xaa可以是任何天然产生的氨基酸
<400> 76
Met Pro Val Asn Ile Lys Xaa Phe Asn Tyr Asn Asp Pro Ile Asn Asn
1 5 10 15
Asp Asp Ile Ile Met Met Glu Pro Phe Asn Asp Pro Gly Pro Gly Thr
20 25 30
Tyr Tyr Lys Ala Phe Arg Ile Ile Asp Arg Ile Trp Ile Val Pro Glu
35 40 45
Arg Phe Thr Tyr Gly Phe Gln Pro Asp Gln Phe Asn Ala Ser Thr Gly
50 55 60
Val Phe Ser Lys Asp Val Tyr Glu Tyr Tyr Asp Pro Thr Tyr Leu Lys
65 70 75 80
Thr Asp Ala Glu Lys Asp Lys Phe Leu Lys Thr Met Ile Lys Leu Phe
85 90 95
Asn Arg Ile Asn Ser Lys Pro Ser Gly Gln Arg Leu Leu Asp Met Ile
100 105 110
Val Asp Ala Ile Pro Tyr Leu Gly Asn Ala Ser Thr Pro Pro Asp Lys
115 120 125
Phe Ala Ala Asn Val Ala Asn Val Ser Ile Asn Lys Lys Ile Ile Gln
130 135 140
Pro Gly Ala Glu Asp Gln Ile Lys Gly Leu Met Thr Asn Leu Ile Ile
145 150 155 160
Phe Gly Pro Gly Pro Val Leu Ser Asp Asn Phe Thr Asp Ser Met Ile
165 170 175
Met Asn Gly His Ser Pro Ile Ser Glu Gly Phe Gly Ala Arg Met Met
180 185 190
Ile Arg Phe Cys Pro Ser Cys Leu Asn Val Phe Asn Asn Val Gln Glu
195 200 205
Asn Lys Asp Thr Ser Ile Phe Ser Arg Arg Ala Tyr Phe Ala Asp Pro
210 215 220
Ala Leu Thr Leu Met His Glu Leu Ile His Val Leu His Gly Leu Tyr
225 230 235 240
Gly Ile Lys Ile Ser Asn Leu Pro Ile Thr Pro Asn Thr Lys Glu Phe
245 250 255
Phe Met Gln His Ser Asp Pro Val Gln Ala Glu Glu Leu Tyr Thr Phe
260 265 270
Gly Gly His Asp Pro Ser Val Ile Ser Pro Ser Thr Asp Met Asn Ile
275 280 285
Tyr Asn Lys Ala Leu Gln Asn Phe Gln Asp Ile Ala Asn Arg Leu Asn
290 295 300
Ile Val Ser Ser Ala Gln Gly Ser Gly Ile Asp Ile Ser Leu Tyr Lys
305 310 315 320
Gln Ile Tyr Lys Asn Lys Tyr Asp Phe Val Glu Asp Pro Asn Gly Lys
325 330 335
Tyr Ser Val Asp Lys Asp Lys Phe Asp Lys Leu Tyr Lys Ala Leu Met
340 345 350
Phe Gly Phe Thr Glu Thr Asn Leu Ala Gly Glu Tyr Gly Ile Lys Thr
355 360 365
Arg Tyr Ser Tyr Phe Ser Glu Tyr Leu Pro Pro Ile Lys Thr Glu Lys
370 375 380
Leu Leu Asp Asn Thr Ile Tyr Thr Gln Asn Glu Gly Phe Asn Ile Ala
385 390 395 400
Ser Lys Asn Leu Lys Thr Glu Phe Asn Gly Gln Asn Lys Ala Val Asn
405 410 415
Lys Glu Ala Tyr Glu Glu Ile Ser Leu Glu His Leu Val Ile Tyr Arg
420 425 430
Ile Ala Met Cys Lys Pro Val Lys Gln Lys Ser Ser Asn Ser Arg Lys
435 440 445
Lys Arg Ser Thr Ser Ser Glu Gln Cys Ile Ile Val Asn Asn Glu Asp
450 455 460
Leu Phe Phe Ile Ala Asn Lys Asp Ser Phe Ser Lys Asp Leu Ala Lys
465 470 475 480
Ala Glu Thr Ile Ala Tyr Asn Thr Gln Asn Asn Thr Ile Glu Asn Asn
485 490 495
Phe Ser Ile Asp Gln Leu Ile Leu Asp Asn Asp Leu Ser Ser Gly Ile
500 505 510
Asp Leu Pro Asn Glu Asn Thr Glu Pro Phe Thr Asn Phe Asp Asp Ile
515 520 525
Asp Ile Pro Val Tyr Ile Lys Gln Ser Ala Leu Lys Lys Ile Phe Val
530 535 540
Asp Gly Asp Ser Leu Phe Glu Tyr Leu His Ala Gln Thr Phe Pro Ser
545 550 555 560
Asn Ile Glu Asn Leu Gln Leu Thr Asn Ser Leu Asn Asp Ala Leu Arg
565 570 575
Asn Asn Asn Lys Val Tyr Thr Phe Phe Ser Thr Asn Leu Val Glu Lys
580 585 590
Ala Asn Thr Val Val Gly Ala Ser Leu Phe Val Asn Trp Val Lys Gly
595 600 605
Val Ile Asp Asp Phe Thr Ser Glu Ser Thr Gln Lys Ser Thr Ile Asp
610 615 620
Lys Val Ser Asp Val Ser Ile Ile Ile Pro Tyr Ile Gly Pro Ala Leu
625 630 635 640
Asn Val Gly Asn Glu Thr Ala Lys Glu Asn Phe Lys Asn Ala Phe Glu
645 650 655
Ile Gly Gly Ala Ala Ile Leu Met Glu Phe Ile Pro Glu Leu Ile Val
660 665 670
Pro Ile Val Gly Phe Phe Thr Leu Glu Ser Tyr Val Gly Asn Lys Gly
675 680 685
His Ile Ile Met Thr Ile Ser Asn Ala Leu Lys Lys Arg Asp Gln Lys
690 695 700
Trp Thr Asp Met Tyr Gly Leu Ile Val Ser Gln Trp Leu Ser Thr Val
705 710 715 720
Asn Thr Gln Phe Tyr Thr Ile Lys Glu Arg Met Tyr Asn Ala Leu Asn
725 730 735
Asn Gln Ser Gln Ala Ile Glu Lys Ile Ile Glu Asp Gln Tyr Asn Arg
740 745 750
Tyr Ser Glu Glu Asp Lys Met Asn Ile Asn Ile Asp Phe Asn Asp Ile
755 760 765
Asp Phe Lys Leu Asn Gln Ser Ile Asn Leu Ala Ile Asn Asn Ile Asp
770 775 780
Asp Phe Ile Asn Gln Cys Ser Ile Ser Tyr Leu Met Asn Arg Met Ile
785 790 795 800
Pro Leu Ala Val Lys Lys Leu Lys Asp Phe Asp Asp Asn Leu Lys Arg
805 810 815
Asp Leu Leu Glu Tyr Ile Asp Thr Asn Glu Leu Tyr Leu Leu Asp Glu
820 825 830
Val Asn Ile Leu Lys Ser Lys Val Asn Arg His Leu Lys Asp Ser Ile
835 840 845
Pro Phe Asp Leu Ser Leu Tyr Thr Lys Asp Thr Ile Leu Ile Gln Val
850 855 860
Phe Asn Asn Tyr Ile Ser Asn Ile Ser Ser Asn Ala Ile Leu Ser Leu
865 870 875 880
Ser Tyr Arg Gly Gly Arg Leu Ile Asp Ser Ser Gly Tyr Gly Ala Thr
885 890 895
Met Asn Val Gly Ser Asp Val Ile Phe Asn Asp Ile Gly Asn Gly Gln
900 905 910
Phe Lys Leu Asn Asn Ser Glu Asn Ser Asn Ile Thr Ala His Gln Ser
915 920 925
Lys Phe Val Val Tyr Asp Ser Met Phe Asp Asn Phe Ser Ile Asn Phe
930 935 940
Trp Val Arg Thr Pro Lys Tyr Asn Asn Asn Asp Ile Gln Thr Tyr Leu
945 950 955 960
Gln Asn Glu Tyr Thr Ile Ile Ser Cys Ile Lys Asn Asp Ser Gly Trp
965 970 975
Lys Val Ser Ile Lys Gly Asn Arg Ile Ile Trp Thr Leu Ile Asp Val
980 985 990
Asn Ala Lys Ser Lys Ser Ile Phe Phe Glu Tyr Ser Ile Lys Asp Asn
995 1000 1005
Ile Ser Asp Tyr Ile Asn Lys Trp Phe Ser Ile Thr Ile Thr Asn
1010 1015 1020
Asp Arg Leu Gly Asn Ala Asn Ile Tyr Ile Asn Gly Ser Leu Lys
1025 1030 1035
Lys Ser Glu Lys Ile Leu Asn Leu Asp Arg Ile Asn Ser Ser Asn
1040 1045 1050
Asp Ile Asp Phe Lys Leu Ile Asn Cys Thr Asp Thr Thr Lys Phe
1055 1060 1065
Val Trp Ile Lys Asp Phe Asn Ile Phe Gly Arg Glu Leu Asn Ala
1070 1075 1080
Thr Glu Val Ser Ser Leu Tyr Trp Ile Gln Ser Ser Thr Asn Thr
1085 1090 1095
Leu Lys Asp Phe Trp Gly Asn Pro Leu Arg Tyr Asp Thr Gln Tyr
1100 1105 1110
Tyr Leu Phe Asn Gln Gly Met Gln Asn Ile Tyr Ile Lys Tyr Phe
1115 1120 1125
Ser Lys Ala Ser Met Gly Glu Thr Ala Pro Arg Thr Asn Phe Asn
1130 1135 1140
Asn Ala Ala Ile Asn Tyr Gln Asn Leu Tyr Leu Gly Leu Arg Phe
1145 1150 1155
Ile Ile Lys Lys Ala Ser Asn Ser Arg Asn Ile Asn Asn Asp Asn
1160 1165 1170
Ile Val Arg Glu Gly Asp Tyr Ile Tyr Leu Asn Ile Asp Asn Ile
1175 1180 1185
Ser Asp Glu Ser Tyr Arg Val Tyr Val Leu Val Asn Ser Lys Glu
1190 1195 1200
Ile Gln Thr Gln Leu Phe Leu Ala Pro Ile Asn Asp Asp Pro Thr
1205 1210 1215
Phe Tyr Asp Val Leu Gln Ile Lys Lys Tyr Tyr Glu Lys Thr Thr
1220 1225 1230
Tyr Asn Cys Gln Ile Leu Cys Glu Lys Asp Thr Lys Thr Phe Gly
1235 1240 1245
Leu Phe Gly Ile Gly Lys Phe Val Lys Asp Tyr Gly Tyr Val Trp
1250 1255 1260
Asp Thr Tyr Asp Asn Tyr Phe Cys Ile Ser Gln Trp Tyr Leu Arg
1265 1270 1275
Arg Ile Ser Glu Asn Ile Asn Lys Leu Arg Leu Gly Cys Asn Trp
1280 1285 1290
Gln Phe Ile Pro Val Asp Glu Gly Trp Thr Glu
1295 1300
<210> 77
<211> 1288
<212> PRT
<213> 人工序列
<220>
<223> 工程化BoNT/X
<400> 77
Met Lys Leu Glu Ile Asn Lys Phe Asn Tyr Asn Asp Pro Ile Asp Gly
1 5 10 15
Ile Asn Val Ile Thr Met Arg Pro Pro Arg His Ser Asp Lys Ile Asn
20 25 30
Lys Gly Lys Gly Pro Phe Lys Ala Phe Gln Val Ile Lys Asn Ile Trp
35 40 45
Ile Val Pro Glu Arg Tyr Asn Phe Thr Asn Asn Thr Asn Asp Leu Asn
50 55 60
Ile Pro Ser Glu Pro Ile Met Glu Ala Asp Ala Ile Tyr Asn Pro Asn
65 70 75 80
Tyr Leu Asn Thr Pro Ser Glu Lys Asp Glu Phe Leu Gln Gly Val Ile
85 90 95
Lys Val Leu Glu Arg Ile Lys Ser Lys Pro Glu Gly Glu Lys Leu Leu
100 105 110
Glu Leu Ile Ser Ser Ser Ile Pro Leu Pro Leu Val Ser Asn Gly Ala
115 120 125
Leu Thr Leu Ser Asp Asn Glu Thr Ile Ala Tyr Gln Glu Asn Asn Asn
130 135 140
Ile Val Ser Asn Leu Gln Ala Asn Leu Val Ile Tyr Gly Pro Gly Pro
145 150 155 160
Asp Ile Ala Asn Asn Ala Thr Tyr Gly Leu Tyr Ser Thr Pro Ile Ser
165 170 175
Asn Gly Glu Gly Thr Leu Ser Glu Val Ser Phe Ser Pro Phe Tyr Leu
180 185 190
Lys Pro Phe Asp Glu Ser Tyr Gly Asn Tyr Arg Ser Leu Val Asn Ile
195 200 205
Val Asn Lys Phe Val Lys Arg Glu Phe Ala Pro Asp Pro Ala Ser Thr
210 215 220
Leu Met His Glu Leu Val His Val Thr His Asn Leu Tyr Gly Ile Ser
225 230 235 240
Asn Arg Asn Phe Tyr Tyr Asn Phe Asp Thr Gly Lys Ile Glu Thr Ser
245 250 255
Arg Gln Gln Asn Ser Leu Ile Phe Glu Glu Leu Leu Thr Phe Gly Gly
260 265 270
Ile Asp Ser Lys Ala Ile Ser Ser Leu Ile Ile Lys Lys Ile Ile Glu
275 280 285
Thr Ala Lys Asn Asn Tyr Thr Thr Leu Ile Ser Glu Arg Leu Asn Thr
290 295 300
Val Thr Val Glu Asn Asp Leu Leu Lys Tyr Ile Lys Asn Lys Ile Pro
305 310 315 320
Val Gln Gly Arg Leu Gly Asn Phe Lys Leu Asp Thr Ala Glu Phe Glu
325 330 335
Lys Lys Leu Asn Thr Ile Leu Phe Val Leu Asn Glu Ser Asn Leu Ala
340 345 350
Gln Arg Phe Ser Ile Leu Val Arg Lys His Tyr Leu Lys Glu Arg Pro
355 360 365
Ile Asp Pro Ile Tyr Val Asn Ile Leu Asp Asp Asn Ser Tyr Ser Thr
370 375 380
Leu Glu Gly Phe Asn Ile Ser Ser Gln Gly Ser Asn Asp Phe Gln Gly
385 390 395 400
Gln Leu Leu Glu Ser Ser Tyr Phe Glu Lys Ile Glu Ser Asn Ala Leu
405 410 415
Arg Ala Phe Ile Lys Ile Cys Pro Arg Asn Gly Leu Lys Gln Lys Ser
420 425 430
Ser Asn Ser Arg Lys Lys Arg Ser Thr Ser Cys Ser Leu Leu Asn Gly
435 440 445
Cys Ile Glu Val Glu Asn Lys Asp Leu Phe Leu Ile Ser Asn Lys Asp
450 455 460
Ser Leu Asn Asp Ile Asn Leu Ser Glu Glu Lys Ile Lys Pro Glu Thr
465 470 475 480
Thr Val Phe Phe Lys Asp Lys Leu Pro Pro Gln Asp Ile Thr Leu Ser
485 490 495
Asn Tyr Asp Phe Thr Glu Ala Asn Ser Ile Pro Ser Ile Ser Gln Gln
500 505 510
Asn Ile Leu Glu Arg Asn Glu Glu Leu Tyr Glu Pro Ile Arg Asn Ser
515 520 525
Leu Phe Glu Ile Lys Thr Ile Tyr Val Asp Lys Leu Thr Thr Phe His
530 535 540
Phe Leu Glu Ala Gln Asn Ile Asp Glu Ser Ile Asp Ser Ser Lys Ile
545 550 555 560
Arg Val Glu Leu Thr Asp Ser Val Asp Glu Ala Leu Ser Asn Pro Asn
565 570 575
Lys Val Tyr Ser Pro Phe Lys Asn Met Ser Asn Thr Ile Asn Ser Ile
580 585 590
Glu Thr Gly Ile Thr Ser Thr Tyr Ile Phe Tyr Gln Trp Leu Arg Ser
595 600 605
Ile Val Lys Asp Phe Ser Asp Glu Thr Gly Lys Ile Asp Val Ile Asp
610 615 620
Lys Ser Ser Asp Thr Leu Ala Ile Val Pro Tyr Ile Gly Pro Leu Leu
625 630 635 640
Asn Ile Gly Asn Asp Ile Arg His Gly Asp Phe Val Gly Ala Ile Glu
645 650 655
Leu Ala Gly Ile Thr Ala Leu Leu Glu Tyr Val Pro Glu Phe Thr Ile
660 665 670
Pro Ile Leu Val Gly Leu Glu Val Ile Gly Gly Glu Leu Ala Arg Glu
675 680 685
Gln Val Glu Ala Ile Val Asn Asn Ala Leu Asp Lys Arg Asp Gln Lys
690 695 700
Trp Ala Glu Val Tyr Asn Ile Thr Lys Ala Gln Trp Trp Gly Thr Ile
705 710 715 720
His Leu Gln Ile Asn Thr Arg Leu Ala His Thr Tyr Lys Ala Leu Ser
725 730 735
Arg Gln Ala Asn Ala Ile Lys Met Asn Met Glu Phe Gln Leu Ala Asn
740 745 750
Tyr Lys Gly Asn Ile Asp Asp Lys Ala Lys Ile Lys Asn Ala Ile Ser
755 760 765
Glu Thr Glu Ile Leu Leu Asn Lys Ser Val Glu Gln Ala Met Lys Asn
770 775 780
Thr Glu Lys Phe Met Ile Lys Leu Ser Asn Ser Tyr Leu Thr Lys Glu
785 790 795 800
Met Ile Pro Lys Val Gln Asp Asn Leu Lys Asn Phe Asp Leu Glu Thr
805 810 815
Lys Lys Thr Leu Asp Lys Phe Ile Lys Glu Lys Glu Asp Ile Leu Gly
820 825 830
Thr Asn Leu Ser Ser Ser Leu Arg Arg Lys Val Ser Ile Arg Leu Asn
835 840 845
Lys Asn Ile Ala Phe Asp Ile Asn Asp Ile Pro Phe Ser Glu Phe Asp
850 855 860
Asp Leu Ile Asn Gln Tyr Lys Asn Glu Ile Glu Asp Tyr Glu Val Leu
865 870 875 880
Asn Leu Gly Ala Glu Asp Gly Lys Ile Lys Asp Leu Ser Gly Thr Thr
885 890 895
Ser Asp Ile Asn Ile Gly Ser Asp Ile Glu Leu Ala Asp Gly Arg Glu
900 905 910
Asn Lys Ala Ile Lys Ile Lys Gly Ser Glu Asn Ser Thr Ile Lys Ile
915 920 925
Ala Met Asn Lys Tyr Leu Arg Phe Ser Ala Thr Asp Asn Phe Ser Ile
930 935 940
Ser Phe Trp Ile Lys His Pro Lys Pro Thr Asn Leu Leu Asn Asn Gly
945 950 955 960
Ile Glu Tyr Thr Leu Val Glu Asn Phe Asn Gln Arg Gly Trp Lys Ile
965 970 975
Ser Ile Gln Asp Ser Lys Leu Ile Trp Tyr Leu Arg Asp His Asn Asn
980 985 990
Ser Ile Lys Ile Val Thr Pro Asp Tyr Ile Ala Phe Asn Gly Trp Asn
995 1000 1005
Leu Ile Thr Ile Thr Asn Asn Arg Ser Lys Gly Ser Ile Val Tyr
1010 1015 1020
Val Asn Gly Ser Lys Ile Glu Glu Lys Asp Ile Ser Ser Ile Trp
1025 1030 1035
Asn Thr Glu Val Asp Asp Pro Ile Ile Phe Arg Leu Lys Asn Asn
1040 1045 1050
Arg Asp Thr Gln Ala Phe Thr Leu Leu Asp Gln Phe Ser Ile Tyr
1055 1060 1065
Arg Lys Glu Leu Asn Gln Asn Glu Val Val Lys Leu Tyr Asn Tyr
1070 1075 1080
Tyr Phe Asn Ser Asn Tyr Ile Arg Asp Ile Trp Gly Asn Pro Leu
1085 1090 1095
Gln Tyr Asn Lys Lys Tyr Tyr Leu Gln Thr Gln Asp Lys Pro Gly
1100 1105 1110
Lys Gly Leu Ile Arg Glu Tyr Trp Ser Ser Phe Gly Tyr Asp Tyr
1115 1120 1125
Val Ile Leu Ser Asp Ser Lys Thr Ile Thr Phe Pro Asn Asn Ile
1130 1135 1140
Arg Tyr Gly Ala Leu Tyr Asn Gly Ser Lys Val Leu Ile Lys Asn
1145 1150 1155
Ser Lys Lys Leu Asp Gly Leu Val Arg Asn Lys Asp Phe Ile Gln
1160 1165 1170
Leu Glu Ile Asp Gly Tyr Asn Met Gly Ile Ser Ala Asp Arg Phe
1175 1180 1185
Asn Glu Asp Thr Asn Tyr Ile Gly Thr Thr Tyr Gly Thr Thr His
1190 1195 1200
Asp Leu Thr Thr Asp Phe Glu Ile Ile Gln Arg Gln Glu Lys Tyr
1205 1210 1215
Arg Asn Tyr Cys Gln Leu Lys Thr Pro Tyr Asn Ile Phe His Lys
1220 1225 1230
Ser Gly Leu Met Ser Thr Glu Thr Ser Lys Pro Thr Phe His Asp
1235 1240 1245
Tyr Arg Asp Trp Val Tyr Ser Ser Ala Trp Tyr Phe Gln Asn Tyr
1250 1255 1260
Glu Asn Leu Asn Leu Arg Lys His Thr Lys Thr Asn Trp Tyr Phe
1265 1270 1275
Ile Pro Lys Asp Glu Gly Trp Asp Glu Asp
1280 1285
<210> 78
<211> 1303
<212> PRT
<213> 人工序列
<220>
<223> 工程化BoNT/X
<400> 78
Met Lys Leu Glu Ile Asn Lys Phe Asn Tyr Asn Asp Pro Ile Asp Gly
1 5 10 15
Ile Asn Val Ile Thr Met Arg Pro Pro Arg His Ser Asp Lys Ile Asn
20 25 30
Lys Gly Lys Gly Pro Phe Lys Ala Phe Gln Val Ile Lys Asn Ile Trp
35 40 45
Ile Val Pro Glu Arg Tyr Asn Phe Thr Asn Asn Thr Asn Asp Leu Asn
50 55 60
Ile Pro Ser Glu Pro Ile Met Glu Ala Asp Ala Ile Tyr Asn Pro Asn
65 70 75 80
Tyr Leu Asn Thr Pro Ser Glu Lys Asp Glu Phe Leu Gln Gly Val Ile
85 90 95
Lys Val Leu Glu Arg Ile Lys Ser Lys Pro Glu Gly Glu Lys Leu Leu
100 105 110
Glu Leu Ile Ser Ser Ser Ile Pro Leu Pro Leu Val Ser Asn Gly Ala
115 120 125
Leu Thr Leu Ser Asp Asn Glu Thr Ile Ala Tyr Gln Glu Asn Asn Asn
130 135 140
Ile Val Ser Asn Leu Gln Ala Asn Leu Val Ile Tyr Gly Pro Gly Pro
145 150 155 160
Asp Ile Ala Asn Asn Ala Thr Tyr Gly Leu Tyr Ser Thr Pro Ile Ser
165 170 175
Asn Gly Glu Gly Thr Leu Ser Glu Val Ser Phe Ser Pro Phe Tyr Leu
180 185 190
Lys Pro Phe Asp Glu Ser Tyr Gly Asn Tyr Arg Ser Leu Val Asn Ile
195 200 205
Val Asn Lys Phe Val Lys Arg Glu Phe Ala Pro Asp Pro Ala Ser Thr
210 215 220
Leu Met His Glu Leu Val His Val Thr His Asn Leu Tyr Gly Ile Ser
225 230 235 240
Asn Arg Asn Phe Tyr Tyr Asn Phe Asp Thr Gly Lys Ile Glu Thr Ser
245 250 255
Arg Gln Gln Asn Ser Leu Ile Phe Glu Glu Leu Leu Thr Phe Gly Gly
260 265 270
Ile Asp Ser Lys Ala Ile Ser Ser Leu Ile Ile Lys Lys Ile Ile Glu
275 280 285
Thr Ala Lys Asn Asn Tyr Thr Thr Leu Ile Ser Glu Arg Leu Asn Thr
290 295 300
Val Thr Val Glu Asn Asp Leu Leu Lys Tyr Ile Lys Asn Lys Ile Pro
305 310 315 320
Val Gln Gly Arg Leu Gly Asn Phe Lys Leu Asp Thr Ala Glu Phe Glu
325 330 335
Lys Lys Leu Asn Thr Ile Leu Phe Val Leu Asn Glu Ser Asn Leu Ala
340 345 350
Gln Arg Phe Ser Ile Leu Val Arg Lys His Tyr Leu Lys Glu Arg Pro
355 360 365
Ile Asp Pro Ile Tyr Val Asn Ile Leu Asp Asp Asn Ser Tyr Ser Thr
370 375 380
Leu Glu Gly Phe Asn Ile Ser Ser Gln Gly Ser Asn Asp Phe Gln Gly
385 390 395 400
Gln Leu Leu Glu Ser Ser Tyr Phe Glu Lys Ile Glu Ser Asn Ala Leu
405 410 415
Arg Ala Phe Ile Lys Ile Cys Pro Arg Asn Gly Leu Leu Tyr Asn Ala
420 425 430
Ile Tyr Arg Asn Ser Lys Gln Lys Ser Ser Asn Ser Arg Lys Lys Arg
435 440 445
Ser Thr Ser Thr Asn Val Ser Tyr Pro Cys Ser Leu Leu Asn Gly Cys
450 455 460
Ile Glu Val Glu Asn Lys Asp Leu Phe Leu Ile Ser Asn Lys Asp Ser
465 470 475 480
Leu Asn Asp Ile Asn Leu Ser Glu Glu Lys Ile Lys Pro Glu Thr Thr
485 490 495
Val Phe Phe Lys Asp Lys Leu Pro Pro Gln Asp Ile Thr Leu Ser Asn
500 505 510
Tyr Asp Phe Thr Glu Ala Asn Ser Ile Pro Ser Ile Ser Gln Gln Asn
515 520 525
Ile Leu Glu Arg Asn Glu Glu Leu Tyr Glu Pro Ile Arg Asn Ser Leu
530 535 540
Phe Glu Ile Lys Thr Ile Tyr Val Asp Lys Leu Thr Thr Phe His Phe
545 550 555 560
Leu Glu Ala Gln Asn Ile Asp Glu Ser Ile Asp Ser Ser Lys Ile Arg
565 570 575
Val Glu Leu Thr Asp Ser Val Asp Glu Ala Leu Ser Asn Pro Asn Lys
580 585 590
Val Tyr Ser Pro Phe Lys Asn Met Ser Asn Thr Ile Asn Ser Ile Glu
595 600 605
Thr Gly Ile Thr Ser Thr Tyr Ile Phe Tyr Gln Trp Leu Arg Ser Ile
610 615 620
Val Lys Asp Phe Ser Asp Glu Thr Gly Lys Ile Asp Val Ile Asp Lys
625 630 635 640
Ser Ser Asp Thr Leu Ala Ile Val Pro Tyr Ile Gly Pro Leu Leu Asn
645 650 655
Ile Gly Asn Asp Ile Arg His Gly Asp Phe Val Gly Ala Ile Glu Leu
660 665 670
Ala Gly Ile Thr Ala Leu Leu Glu Tyr Val Pro Glu Phe Thr Ile Pro
675 680 685
Ile Leu Val Gly Leu Glu Val Ile Gly Gly Glu Leu Ala Arg Glu Gln
690 695 700
Val Glu Ala Ile Val Asn Asn Ala Leu Asp Lys Arg Asp Gln Lys Trp
705 710 715 720
Ala Glu Val Tyr Asn Ile Thr Lys Ala Gln Trp Trp Gly Thr Ile His
725 730 735
Leu Gln Ile Asn Thr Arg Leu Ala His Thr Tyr Lys Ala Leu Ser Arg
740 745 750
Gln Ala Asn Ala Ile Lys Met Asn Met Glu Phe Gln Leu Ala Asn Tyr
755 760 765
Lys Gly Asn Ile Asp Asp Lys Ala Lys Ile Lys Asn Ala Ile Ser Glu
770 775 780
Thr Glu Ile Leu Leu Asn Lys Ser Val Glu Gln Ala Met Lys Asn Thr
785 790 795 800
Glu Lys Phe Met Ile Lys Leu Ser Asn Ser Tyr Leu Thr Lys Glu Met
805 810 815
Ile Pro Lys Val Gln Asp Asn Leu Lys Asn Phe Asp Leu Glu Thr Lys
820 825 830
Lys Thr Leu Asp Lys Phe Ile Lys Glu Lys Glu Asp Ile Leu Gly Thr
835 840 845
Asn Leu Ser Ser Ser Leu Arg Arg Lys Val Ser Ile Arg Leu Asn Lys
850 855 860
Asn Ile Ala Phe Asp Ile Asn Asp Ile Pro Phe Ser Glu Phe Asp Asp
865 870 875 880
Leu Ile Asn Gln Tyr Lys Asn Glu Ile Glu Asp Tyr Glu Val Leu Asn
885 890 895
Leu Gly Ala Glu Asp Gly Lys Ile Lys Asp Leu Ser Gly Thr Thr Ser
900 905 910
Asp Ile Asn Ile Gly Ser Asp Ile Glu Leu Ala Asp Gly Arg Glu Asn
915 920 925
Lys Ala Ile Lys Ile Lys Gly Ser Glu Asn Ser Thr Ile Lys Ile Ala
930 935 940
Met Asn Lys Tyr Leu Arg Phe Ser Ala Thr Asp Asn Phe Ser Ile Ser
945 950 955 960
Phe Trp Ile Lys His Pro Lys Pro Thr Asn Leu Leu Asn Asn Gly Ile
965 970 975
Glu Tyr Thr Leu Val Glu Asn Phe Asn Gln Arg Gly Trp Lys Ile Ser
980 985 990
Ile Gln Asp Ser Lys Leu Ile Trp Tyr Leu Arg Asp His Asn Asn Ser
995 1000 1005
Ile Lys Ile Val Thr Pro Asp Tyr Ile Ala Phe Asn Gly Trp Asn
1010 1015 1020
Leu Ile Thr Ile Thr Asn Asn Arg Ser Lys Gly Ser Ile Val Tyr
1025 1030 1035
Val Asn Gly Ser Lys Ile Glu Glu Lys Asp Ile Ser Ser Ile Trp
1040 1045 1050
Asn Thr Glu Val Asp Asp Pro Ile Ile Phe Arg Leu Lys Asn Asn
1055 1060 1065
Arg Asp Thr Gln Ala Phe Thr Leu Leu Asp Gln Phe Ser Ile Tyr
1070 1075 1080
Arg Lys Glu Leu Asn Gln Asn Glu Val Val Lys Leu Tyr Asn Tyr
1085 1090 1095
Tyr Phe Asn Ser Asn Tyr Ile Arg Asp Ile Trp Gly Asn Pro Leu
1100 1105 1110
Gln Tyr Asn Lys Lys Tyr Tyr Leu Gln Thr Gln Asp Lys Pro Gly
1115 1120 1125
Lys Gly Leu Ile Arg Glu Tyr Trp Ser Ser Phe Gly Tyr Asp Tyr
1130 1135 1140
Val Ile Leu Ser Asp Ser Lys Thr Ile Thr Phe Pro Asn Asn Ile
1145 1150 1155
Arg Tyr Gly Ala Leu Tyr Asn Gly Ser Lys Val Leu Ile Lys Asn
1160 1165 1170
Ser Lys Lys Leu Asp Gly Leu Val Arg Asn Lys Asp Phe Ile Gln
1175 1180 1185
Leu Glu Ile Asp Gly Tyr Asn Met Gly Ile Ser Ala Asp Arg Phe
1190 1195 1200
Asn Glu Asp Thr Asn Tyr Ile Gly Thr Thr Tyr Gly Thr Thr His
1205 1210 1215
Asp Leu Thr Thr Asp Phe Glu Ile Ile Gln Arg Gln Glu Lys Tyr
1220 1225 1230
Arg Asn Tyr Cys Gln Leu Lys Thr Pro Tyr Asn Ile Phe His Lys
1235 1240 1245
Ser Gly Leu Met Ser Thr Glu Thr Ser Lys Pro Thr Phe His Asp
1250 1255 1260
Tyr Arg Asp Trp Val Tyr Ser Ser Ala Trp Tyr Phe Gln Asn Tyr
1265 1270 1275
Glu Asn Leu Asn Leu Arg Lys His Thr Lys Thr Asn Trp Tyr Phe
1280 1285 1290
Ile Pro Lys Asp Glu Gly Trp Asp Glu Asp
1295 1300
Claims (32)
1.工程化的梭菌神经毒素，其包含弗林蛋白酶切割位点，其中在所述弗林蛋白酶切割位点处的切割导致产生双链形式的工程化梭菌神经毒素。
2.根据权利要求1的工程化的梭菌神经毒素，其中所述弗林蛋白酶切割位点包含氨基酸序列Arg-Xaa-Xaa-Arg(SEQ ID NO:1)，优选Arg-Xaa-Lys/Arg-Arg(SEQ ID NO:2和3)，甚至更优选Arg-Lys-Lys-Arg(SEQ ID NO:4)，且甚至更优选KQKSSNSRKKR(SEQ ID NO:5)。
3.根据权利要求1或2的工程化的梭菌神经毒素，其中所述工程化梭菌神经毒素包含外源性活化环，其包含SEQ ID NO:14至22中的任一项或由其组成，优选SEQ ID NO:22。
4.根据前述任一项权利要求的工程化的梭菌神经毒素，其中梭菌神经毒素的内源性活化环或其部分已被弗林蛋白酶切割位点替代。
5.根据权利要求4的工程化的梭菌神经毒素，其中内源性神经毒素活化环是选自SEQID NO:34至57的一项或多项。
6.根据前述任一项权利要求的工程化的梭菌神经毒素，其中所述梭菌神经毒素是：
(a)肉毒神经毒素(BoNT)血清型A、血清型B、血清型C、血清型D、血清型E、血清型F、血清型G或血清型X，或破伤风神经毒素(TeNT)；或
(b)嵌合BoNT或杂合BoNT。
7.根据权利要求6的工程化梭菌神经毒素，其为BoNT/A，任选为BoNT/A1。
8.根据前述任一项权利要求的工程化梭菌神经毒素，其为：
(a)由与SEQ ID NO:23具有至少70％序列同一性的核苷酸序列编码；和/或
(b)包含与SEQ ID NO:24或70至78中的一项或多项具有至少70％序列同一性的多肽序列的单链梭菌神经毒素。
9.根据前述任一项权利要求的工程化的梭菌神经毒素，其是重新靶向的梭菌神经毒素，其中梭菌神经毒素的内源性HC或HCC被外源靶向部分(TM)替代。
10.包含弗林蛋白酶切割位点的工程化BoNT/A，其包含与SEQ ID NO:24具有至少70％序列同一性，优选至少80％，更优选至少90％，甚至更优选至少95％序列同一性的多肽序列。
11.一种用于将根据权利要求1至9任一项的工程化梭菌神经毒素或根据权利要求10的工程化BoNT/A蛋白水解加工成相应的双链梭菌神经毒素或BoNT/A的方法，所述方法包括使工程化梭菌神经毒素或工程化BoNT/A与弗林蛋白酶接触，从而产生双链梭菌神经毒素或BoNT/A。
12.可通过权利要求11的方法获得的双链梭菌神经毒素或BoNT/A。
13.一种多核苷酸，其编码如权利要求1至9任一项中限定的工程化梭菌神经毒素或根据权利要求10的工程化BoNT/A。
14.一种表达载体，其包含与启动子可操作地连接的如权利要求13所述的多核苷酸。
15.根据权利要求13的多核苷酸或根据权利要求14的表达载体，其中所述多核苷酸或表达载体：
(a)包含与SEQ ID NO:23具有至少70％序列同一性的核苷酸序列；和/或
(b)编码与SEQ ID NO:24或70至78中的一项或多项具有至少70％序列同一性的多肽序列。
16.一种产生如权利要求1至9任一项中限定的工程化梭菌神经毒素或根据权利要求10的工程化BoNT/A的方法，其包括在细胞中表达如权利要求13或15中限定的多核苷酸或如权利要求14或15中限定的表达载体，并回收表达的工程化梭菌神经毒素或工程化BoNT/A的步骤。
17.权利要求16的方法，其还包括将如权利要求13或15中限定的多核苷酸或如权利要求14或15中限定的表达载体引入细胞中的步骤。
18.一种细胞，其表达如权利要求1至9任一项中限定的工程化梭菌神经毒素或根据权利要求10的工程化BoNT/A。
19.权利要求18的细胞，其包含如权利要求13或15中限定的多核苷酸，或如权利要求14或15中限定的表达载体。
20.一种药物组合物，其包含如权利要求1至9任一项中限定的工程化梭菌神经毒素、根据权利要求10的工程化BoNT/A或如权利要求12中限定的双链梭菌神经毒素或双链BoNT/A，以及药学上可接受的载体、赋形剂、稀释剂、佐剂、推进剂和/或盐。
21.如权利要求1至9任一项中限定的工程化梭菌神经毒素、根据权利要求10的工程化BoNT/A、如权利要求12中限定的双链梭菌神经毒素或双链BoNT/A、或如权利要求20中限定的药物组合物，用于预防或治疗适用肉毒神经毒素治疗的疾病或病症的方法中，其中任选地，所述疾病或病症选自与不合需要的免疫分泌相关的病症、斜视(strabismus)、眼睑痉挛、斜视(squint)、肌张力障碍(例如痉挛性肌张力障碍、口下颌肌张力障碍，局灶性肌张力异常、迟发性肌张力不良、喉部肌张力障碍和肢体肌张力障碍以及颈颈肌张力障碍)、斜颈(例如痉挛型斜颈)、受益于细胞/肌肉丧失能力(经由SNARE下调或失活)的美容治疗(美容)应用、眼运动的神经肌肉紊乱或病况(如伴行斜视、垂直斜视、侧直肌麻痹、眼球震颤、甲状腺功能异常肌病)、作家痉挛、磨牙症、Wilson病、震颤、抽搐、节段性肌阵挛、痉挛，由于慢性多发性硬化症引起的痉挛、导致膀胱控制异常的痉挛、男性意像(animus)、背部痉挛、抽筋、骨盆提肌综合征(levator pelvic syndrome)、脊柱裂、迟发性运动障碍、帕金森病、口吃、面肌痉挛、眼睑障碍、脑瘫、局灶性痉挛、痉挛性结肠炎、神经源性膀胱、盆底失弛缓综合征(anismus)、肢体僵直(limb spasticity)、抽动、震颤、磨牙症、肛裂、贲门失弛缓症、吞咽困难、流泪、多汗症、唾液过多、胃肠道分泌物过多、肌肉疼痛(如肌肉痉挛引起的疼痛)、头痛(如紧张性头痛或偏头痛)、幻痛(例如，幻肢痛)、眉沟、皮肤皱纹、癌症、子宫疾病、泌尿生殖器病症、泌尿生殖神经系统疾病、膀胱疼痛综合征、间质性膀胱炎、慢性神经源性炎症和平滑肌障碍。
22.如权利要求1至9任一项中限定的工程化梭菌神经毒素、根据权利要求10的工程化BoNT/A、如权利要求12中限定的双链梭菌神经毒素或双链BoNT/A或如权利要求20中限定的药物组合物在制备用于预防或治疗适用肉毒神经毒素疗法的疾病或病症的药物中的用途，其中任选地，所述疾病或病症选自与不合需要的免疫分泌相关的病症、斜视(strabismus)、眼睑痉挛、斜视(squint)、肌张力障碍(例如痉挛性肌张力障碍、口下颌肌张力障碍，局灶性肌张力异常、迟发性肌张力不良、喉部肌张力障碍和肢体肌张力障碍以及颈颈肌张力障碍)、斜颈(例如痉挛型斜颈)、受益于细胞/肌肉丧失能力(经由SNARE下调或失活)的美容治疗(美容)应用、眼运动的神经肌肉紊乱或病况(如伴行斜视、垂直斜视、侧直肌麻痹、眼球震颤、甲状腺功能异常肌病)、作家痉挛、磨牙症、Wilson病、震颤、抽搐、节段性肌阵挛、痉挛，由于慢性多发性硬化症引起的痉挛、导致膀胱控制异常的痉挛、男性意像(animus)、背部痉挛、抽筋、骨盆提肌综合征(levator pelvic syndrome)、脊柱裂、迟发性运动障碍、帕金森病、口吃、面肌痉挛、眼睑障碍、脑瘫、局灶性痉挛、痉挛性结肠炎、神经源性膀胱、盆底失弛缓综合征(anismus)、肢体僵直(limb spasticity)、抽动、震颤、磨牙症、肛裂、贲门失弛缓症、吞咽困难、流泪、多汗症、唾液过多、胃肠道分泌物过多、肌肉疼痛(如肌肉痉挛引起的疼痛)、头痛(如紧张性头痛或偏头痛)、幻痛(例如，幻肢痛)、眉沟、皮肤皱纹、癌症、子宫疾病、泌尿生殖器病症、泌尿生殖神经系统疾病、膀胱疼痛综合征、间质性膀胱炎、慢性神经源性炎症和平滑肌障碍。
23.一种美容组合物，其包含如权利要求1至9任一项中限定的工程化梭菌神经毒素、根据权利要求10的工程化BoNT/A或如权利要求12中限定的双链梭菌神经毒素或双链BoNT/A，以及美容上可接受的载体、赋形剂、稀释剂、佐剂、推进剂和/或盐。
24.如权利要求23中限定的美容组合物的用途，用于预防或减轻适用应用肉毒神经毒素的美容适应症。
25.一种用于将单链梭菌神经毒素蛋白水解加工成相应的双链梭菌神经毒素的方法，所述方法包括：
(a)提供单链梭菌神经毒素；和
(b)使单链梭菌神经毒素与弗林蛋白酶接触；
其中单链梭菌神经毒素具有包含多肽序列Arg-Xaa-Xaa-Arg(SEQ ID NO:1)或由其组成的活化环；和
其中弗林蛋白酶水解活化环的肽键，从而产生双链梭菌神经毒素。
26.根据权利要求25的方法，其中活化环包含：
(a)Arg-Xaa-Lys/Arg-Arg(SEQ ID NO:2或3)；
(b)Arg-Lys-Lys-Arg(SEQ ID NO:4)；和/或
(c)KQKSSNSRKKR(SEQ ID NO:5)
或由其组成。
27.根据权利要求25或26的方法，其中单链梭菌神经毒素：
(a)是如权利要求1至9任一项中限定的工程化梭菌神经毒素；
(b)由与SEQ ID NO:23具有至少70％序列同一性的核苷酸序列编码；
(c)包含与SEQ ID NO:24或70至78中的一项或多项具有至少70％序列同一性的多肽序列。
28.梭菌神经毒素或包含所述梭菌神经毒素的药物组合物，用于预防或治疗适用肉毒神经毒素疗法的疾病或病症的方法中，其中梭菌神经毒素以单链形式施用于受试者。
29.根据权利要求28使用的梭菌神经毒素或药物组合物用于所述方法中，其中梭菌神经毒素或药物组合物基本上不含双链形式的梭菌神经毒素。
30.根据权利要求29使用的梭菌神经毒素或药物组合物用于所述方法中，其中梭菌神经毒素或药物组合物包含小于400pg双链梭菌神经毒素/100ng单链梭菌神经毒素，或小于300pg双链梭菌神经毒素/100ng单链梭菌神经毒素，或小于200pg双链梭菌神经毒素/100ng单链梭菌神经毒素，或小于100pg双链梭菌神经毒素/100ng单链梭菌神经毒素，或小于50pg双链梭菌神经毒素/100ng单链梭菌神经毒素。
31.根据权利要求28至30任一项的梭菌神经毒素或药物组合物用于所述方法中，其中所述疾病或病症选自与不合需要的免疫分泌相关的病症、斜视(strabismus)、眼睑痉挛、斜视(squint)、肌张力障碍(例如痉挛性肌张力障碍、口下颌肌张力障碍，局灶性肌张力异常、迟发性肌张力不良、喉部肌张力障碍和肢体肌张力障碍以及颈颈肌张力障碍)、斜颈(例如痉挛型斜颈)、受益于细胞/肌肉丧失能力(经由SNARE下调或失活)的美容治疗(美容)应用、眼运动的神经肌肉紊乱或病况(如伴行斜视、垂直斜视、侧直肌麻痹、眼球震颤、甲状腺功能异常肌病)、作家痉挛、磨牙症、Wilson病、震颤、抽搐、节段性肌阵挛、痉挛，由于慢性多发性硬化症引起的痉挛、导致膀胱控制异常的痉挛、男性意像(animus)、背部痉挛、抽筋、骨盆提肌综合征(levator pelvic syndrome)、脊柱裂、迟发性运动障碍、帕金森病、口吃、面肌痉挛、眼睑障碍、脑瘫、局灶性痉挛、痉挛性结肠炎、神经源性膀胱、盆底失弛缓综合征(anismus)、肢体僵直(limb spasticity)、抽动、震颤、磨牙症、肛裂、贲门失弛缓症、吞咽困难、流泪、多汗症、唾液过多、胃肠道分泌物过多、肌肉疼痛(如肌肉痉挛引起的疼痛)、头痛(如紧张性头痛或偏头痛)、幻痛(例如，幻肢痛)、眉沟、皮肤皱纹、癌症、子宫疾病、泌尿生殖器病症、泌尿生殖神经系统疾病、膀胱疼痛综合征、间质性膀胱炎、慢性神经源性炎症和平滑肌障碍。
32.包含单链梭菌神经毒素和美容上可接受的载体、赋形剂、稀释剂、佐剂、推进剂和/或盐的美容组合物的用途，用于预防或减轻适用应用肉毒神经毒素的美容适应症，其中单链梭菌神经毒素以单链形式施用于受试者。
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| MX2019000151A (es) | 2016-07-08 | 2019-08-29 | Childrens Medical Center | Una neurotoxina botulinica novedosa y sus derivados. |
| GB201815817D0 (en) | 2018-09-28 | 2018-11-14 | Ispen Biopharm Ltd | Clostridial neurotoxins comprising and exogenous activation loop |
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2021
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| JP2024510786A (ja) | 2024-03-11 |
| WO2022200809A1 (en) | 2022-09-29 |
| EP4312964A1 (en) | 2024-02-07 |
| AU2022242859A1 (en) | 2023-08-17 |
| GB202104294D0 (en) | 2021-05-12 |
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