CN115551551A - 抗感染双环肽缀合物 - Google Patents
抗感染双环肽缀合物 Download PDFInfo
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- CN115551551A CN115551551A CN202180030888.1A CN202180030888A CN115551551A CN 115551551 A CN115551551 A CN 115551551A CN 202180030888 A CN202180030888 A CN 202180030888A CN 115551551 A CN115551551 A CN 115551551A
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Classifications
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- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/21—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Pseudomonadaceae (F)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/21—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Pseudomonadaceae (F)
- C07K14/212—Moraxellaceae, e.g. Acinetobacter, Moraxella, Oligella, Psychrobacter
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- C07K14/24—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
本发明涉及多肽,其与分子支架共价结合,使得在支架的连接点之间对向存在两个或更多个肽环。特别地,本发明的双环肽与载体肽缀合以大大增强细菌细胞杀伤活性。更特别地,本发明描述了作为青霉素结合蛋白(PBP,如PBP3和PBP3a)的高亲和力结合物的肽。本发明还包括包含所述缀合物的药物组合物,和所述缀合物在抑制或治疗由细菌感染介导的疾病或疾患中的用途,或用于对有感染风险的受试者提供预防的用途。
Description
技术领域
本发明涉及多肽,其与分子支架共价结合,使得在支架的连接点之间对向存在(subtend)两个或更多个肽环。特别地,本发明的双环肽与载体肽缀合以大大增强细菌细胞杀伤活性。更特别地,本发明描述了作为青霉素结合蛋白(PBP,如PBP3和PBP3a)的高亲和力结合物的肽。本发明还包括包含所述缀合物的药物组合物,和所述缀合物在抑制或治疗由细菌感染介导的疾病或疾患中的用途,或用于对有感染风险的受试者提供预防的用途。
背景技术
环肽能够以高亲和力和靶标特异性与蛋白质靶标结合,因此是对于治疗剂开发有吸引力的分子类别。事实上,临床上已经成功使用了几种环肽,例如抗菌肽万古霉素、免疫抑制剂环孢霉素或抗癌药奥曲肽(Driggers等人(2008),Nat Rev Drug Discov 7(7),608-24)。良好的结合特性是由于肽与靶标之间形成的相对较大的相互作用表面以及环状结构的构象柔韧性降低所致。通常,大环与数百平方埃的表面结合,例如环肽CXCR4拮抗剂CVX15(Wu等人(2007),Science 330,1066-71)、具有与整联蛋白αVb3()结合的Arg-Gly-Asp基序的环肽(Xiong等人(2002),Science 296(5565),151-5)或结合尿激酶型纤溶酶原激活因子的环肽抑制剂upain-1(Zhao等人(2007),J Struct Biol 160(1),1-10)。
由于其环状构型,肽大环比线性肽柔韧性差,导致与靶标结合后熵损失较小,并导致更高的结合亲和力。与线性肽相比,降低的柔韧性还导致锁定靶标特异性构象,增加结合特异性。这种作用已通过一种基质金属蛋白酶8(MMP-8)的有效的和选择性抑制剂得到了例证,该抑制剂在开环时失去相对于其他MMP的选择性(Cherney等人(1998),J Med Chem 41(11),1749-51)。通过大环化获得的有利的结合性质在具有多于一个肽环的多环肽中更为显著,例如在万古霉素、乳酸链球菌肽和放线菌素中。
不同的研究团队先前已将具有半胱氨酸残基的多肽系于(tether)一个合成的分子结构上(Kemp和McNamara(1985),J.Org.Chem;Timmerman等人(2005),ChemBioChem)。Meloen和同事已使用三(溴甲基)苯和相关分子将多个肽环快速定量地环化到合成支架上,以结构模拟蛋白质表面(Timmerman等人(2005),ChemBioChem)。WO 2004/077062和WO2006/078161中公开了用于生成候选药物化合物的方法,其中所述化合物是通过将包含半胱氨酸的多肽连接到分子支架上而生成的,所述分子支架例如为三(溴甲基)苯。
已经开发了基于噬菌体展示的组合方法以生成和筛选针对目标靶标的双环肽的大型文库(Heinis等人(2009),Nat Chem Biol 5(7),502-7和WO 2009/098450)。简而言之,在噬菌体上展示了包含三个半胱氨酸残基和两个六随机氨基酸的区域(Cys-(Xaa)6-Cys-(Xaa)6-Cys)的线性肽的组合文库,并通过将半胱氨酸侧链共价连接至小分子支架来进行环化。
发明内容
根据本发明的第一方面,提供了一种抗感染肽缀合物,其包含:
(i)双环肽配体,其能够结合一个或多个青霉素结合蛋白(PBP),其包含多肽和分子支架,所述多肽包含被至少两个环序列隔开的至少三个半胱氨酸残基,并且所述分子支架与所述多肽的半胱氨酸残基形成共价键,使得在分子支架上形成至少两个多肽环;和
(ii)载体肽。
根据本发明的进一步的方面,提供了一种药物组合物,其包含如本文所定义的缀合物,与一种或多种药学上可接受的赋形剂组合。
根据本发明的进一步的方面,提供了如本文所定义的缀合物用于抑制或治疗细菌感染介导的疾病或疾患的用途,或用于对有感染风险的受试者提供预防的用途。
具体实施方式
根据本发明的第一方面,提供了一种抗感染肽缀合物,其包含:
(i)双环肽配体,其能够结合一个或多个青霉素结合蛋白(PBP),其包含多肽和分子支架,所述多肽包含被至少两个环序列隔开的至少三个半胱氨酸残基,并且所述分子支架与所述多肽的半胱氨酸残基形成共价键,使得在分子支架上形成至少两个多肽环;和
(ii)载体肽。
双环肽配体
在一个实施方案中,所述环序列包含4或5个氨基酸。
在进一步的实施方案中,所述环序列包含被两个环序列隔开的三个半胱氨酸残基,所述两个环序列均由4个氨基酸组成。
在进一步的实施方案中,所述环序列包含被两个环序列隔开的三个半胱氨酸残基,所述两个环序列的一个由4个氨基酸组成,另一个由5个氨基酸组成。
本文提及的PBP包括“青霉素结合蛋白”,其可以存在于任何细菌物种中。在一个实施方案中,所述PBP是存在于一种或多种病原细菌物种内的PBP。在进一步的实施方案中,所述一种或多种病原细菌物种选自以下任一项:鲍曼不动杆菌(Acinetobacter baumannii)、炭疽杆菌(Bacillus anthracis)、百日咳博德特氏菌(Bordetella pertussis)、伯氏疏螺旋体(Borrelia burgdorferi)、流产布鲁氏菌(Brucella abortus)、犬布鲁氏菌(Brucellacanis)、马耳他布鲁氏菌(Brucella melitensis)、猪布鲁氏菌(Brucella suis)、空肠弯曲杆菌(Campylobacter jejuni)、肺炎衣原体(Chlamydia pneumonia)、沙眼衣原体(Chlamydia trachomatis)、鹦鹉热衣原体(Chlamydophila psittaci)、肉毒梭菌(Clostridium botulinum)、艰难梭菌(Clostridium difficile)、产气荚膜梭菌(Clostridium perfringens)、破伤风梭菌(Clostrium tetani)、白喉棒状杆菌(Corynebacterium diphtheriae)、棘球绦虫(Echinococcus)、粪肠球菌(Enterococcusfaecalis)、屎肠球菌(Enterococcus faecium)、大肠杆菌(Escherichia coli)(如产肠毒素大肠杆菌、肠致病性大肠杆菌、肠出血大肠杆菌或肠聚集性大肠杆菌)、土拉弗朗西斯菌(Francisella tularensis)、流感嗜血杆菌(Haemophilus influenzae)、幽门螺杆菌(Helicobacter pylori)、肺炎克雷伯菌(Klebsiella pneumoniae)、嗜肺军团菌(Legionella pneumophila)、问号钩端螺旋体(Leptospira interrogans)、单核细胞增生李斯特菌(Listeria monocytogenes)、麻风分枝杆菌(Mycobacterium leprae)、结核分枝杆菌(Mycobacterium tuberculosis)、溃疡分枝杆菌(Mycobacterium ulcerans)、肺炎支原体(Mycoplasma pneumonia)、淋病奈瑟菌(Neisseria gonorrhoeae)、脑膜炎奈瑟菌(Neisseria meningitides)、肺炎球菌(Pneumococcus)、铜绿假单胞菌(Pseudomonasaeruginosa)、立克次氏体(Rickettsia rickettsia)、沙门氏菌(如邦戈尔沙门氏菌(Salmonella bongori)、肠沙门氏菌(Salmonella enterica)、地下沙门氏菌(Salmonellasubterranean)、伤寒沙门氏菌(Salmonella typhi)或鼠伤寒沙门氏菌(Salmonellatyphimurium))、志贺氏菌(如索氏志贺氏菌(Shigella sonnei)或痢疾志贺氏菌(Shigelladysenteriae))、金黄色葡萄球菌(Staphylococcus aureus)(如MRSA)、表皮葡萄球菌(Staphylococcus epidermidis)、腐生葡萄球菌(Staphylococcus saprophyticus)、无乳链球菌(Streptococcus agalactiae)、肺炎链球菌(Streptococcus pneumoniae)、酿脓链球菌(Streptococcus pyogenes)、苍白密螺旋体(Treponema pallidum)、霍乱弧菌(Vibriocholerae)或鼠疫耶尔森菌(Yersinia pestis)。
在一个实施方案中,所述PBP是存在于大肠杆菌内的PBP3。
在可选的实施方案中,所述PBP是存在于铜绿假单胞菌内的PBP3。在进一步的实施方案中,存在于铜绿假单胞菌内的PBP选自PBP3和PBP3a。在更进一步的实施方案中,存在于铜绿假单胞菌内的PBP是PBP3。
在可选的实施方案中,所述PBP是存在于鲍曼不动杆菌内的PBP3。
在一个实施方案中,细胞分裂需要PBP,如FtsI。在进一步的实施方案中,所述FtsI存在于大肠杆菌、鲍曼不动杆菌或铜绿假单胞菌中,并且称为PBP3。因此,根据本发明的某些实施方案,PBP3是FtsI。
在一个实施方案中,所述PBP是大肠杆菌PBP3,所述双环肽配体包含选自以下的氨基酸序列:
CiSFPKCiiPWVEGCiii(SEQ ID NO:1);
CiRTFGCiiWWEGCiii(SEQ ID NO:2);
CiSFPKCiiPWVEGCiii(SEQ ID NO:3);
CiIYPKCiiPWVEGCiii(SEQ ID NO:4);
CiYFPKCiiPWVEGCiii(SEQ ID NO:5);
CiHFPKCiiPWVEGCiii(SEQ ID NO:6);
CiKFPVCiiPWVEYCiii(SEQ ID NO:7);
CiVYPKCiiPWVEGCiii(SEQ ID NO:8);
CiRFPKCiiPWVEGCiii(SEQ ID NO:9);
CiSFPACiiPWVEGCiii(SEQ ID NO:10);和
CiFWGSCiiVPEPKCiii(SEQ ID NO:11);
或其药学上可接受的盐,其中Ci、Cii和Ciii表示第一、第二和第三半胱氨酸残基。
在进一步的实施方案中,所述PBP是大肠杆菌PBP3,所述双环肽配体另外包含N-和/或C-末端添加,并且包含选自以下的氨基酸序列:
A-(SEQ ID NO:1)-A(在本文中称为BCY12130);
A-(SEQ ID NO:2)-A(在本文中称为BCY12132);
Ac-(SEQ ID NO:3)(在本文中称为BCY12742);
A-(SEQ ID NO:4)-A(在本文中称为BCY13769);
A-(SEQ ID NO:5)-A(在本文中称为BCY13756);
A-(SEQ ID NO:6)-A(在本文中称为BCY13754);
A-(SEQ ID NO:7)-A(在本文中称为BCY13747);
A-(SEQ ID NO:8)-A(在本文中称为BCY13768);
A-(SEQ ID NO:9)-A(在本文中称为BCY13766);
Ac-(SEQ ID NO:10)(在本文中称为BCY14682);和
A-(SEQ ID NO:11)-A(在本文中称为BCY14681);
或其药学上可接受的盐。
在一个实施方案中,所述双环肽配体另外包含用于促进与载体肽缀合的部分。这种缀合促进部分包括K(PYA)残基,其中PYA表示4-戊烯酸残基、或由6个乙二醇残基和末端叠氮基组成的连接基团(在本文中称为Peg6-叠氮化物)。
在进一步的实施方案中,所述双环肽配体另外包含在缀合促进部分和双环肽之间的间隔子。这种间隔子包括具有多个肌氨酸(Sar)残基的间隔子,即Sar5或Sar6。
因此,在进一步的实施方案中,所述PBP是大肠杆菌PBP3,所述双环肽配体除了缀合促进部分和任选的间隔子之外另外包含N-和/或C-末端添加,并且包含选自以下的氨基酸序列:
A-(SEQ ID NO:1)-A-K(PYA)(在本文中称为BCY12805);
(PYA)G-Sar5)-A-(SEQ ID NO:1)-A-K(PYA)(在本文中称为BCY12821);
A-(SEQ ID NO:1)-A-Sar6-K(PYA)(在本文中称为BCY12673);
(PYA)K-A-(SEQ ID NO:1)-A(在本文中称为BCY13416);
(PYA)-A-(SEQ ID NO:1)-A(在本文中称为BCY12824);
A-(SEQ ID NO:2)-A-Sar6-K(PYA)(在本文中称为BCY12674);
Ac-(SEQ ID NO:3)-Lys4(Peg6-叠氮化物)(在本文中称为BCY14287);
Ac-(SEQ ID NO:3)-K(PYA)(在本文中称为BCY13812);
A-(SEQ ID NO:4)-A-K(PYA)(在本文中称为BCY14369);
A-(SEQ ID NO:5)-A-K(PYA)(在本文中称为BCY14278);
A-(SEQ ID NO:6)-A-K(PYA)(在本文中称为BCY14277);
A-(SEQ ID NO:7)-A-K(PYA)(在本文中称为BCY14276);
A-(SEQ ID NO:8)-A-K(PYA)(在本文中称为BCY14280);
A-(SEQ ID NO:9)-A-K(PYA)(在本文中称为BCY14279);
Ac-(SEQ ID NO:10)-K(PYA)(在本文中称为BCY13813);
(PYA)K-A-(SEQ ID NO:11)-A(在本文中称为BCY13415);
A-(SEQ ID NO:11)-A-K(PYA)(在本文中称为BCY13417);和
A-(SEQ ID NO:11)-A-Sar6-K(PYA)(在本文中称为BCY12804);
或其药学上可接受的盐。
在更进一步的实施方案中,所述PBP是大肠杆菌PBP3,所述双环肽配体除了缀合促进部分和任选的间隔子之外另外包含N-和/或C-末端添加,并且包含氨基酸序列:
A-(SEQ ID NO:1)-A-K(PYA)(在本文中称为BCY12805);
或其药学上可接受的盐。
载体肽
在一个实施方案中,所述载体肽包含线性肽。
在一个实施方案中,所述载体肽包含介于3和15个之间的氨基酸。在进一步的实施方案中,所述载体肽包含介于4和12个之间的氨基酸。在更进一步的实施方案中,所述载体肽的长度为4、7、8、10、11或12个氨基酸。
在一个实施方案中,所述载体肽选自以下肽中的一种:
KSLRRVWRSWR(SEQ ID NO:12);
[dK][dS][dL][dR][dR][dV][dW][dR][dS][dW][dR](SEQ ID NO:13);
KSL[HArg][HArg]VW[HArg]SW[HArg](SEQ ID NO:14);
[dR][dW][dS][dR][dW][dV][dR][dR][dL][dS][dK](SEQ ID NO:15);
VKLFPVKLFP(SEQ ID NO:16);
SLLSLIRKLIT(SEQ ID NO:17);
FFFLSRIFGK(SEQ ID NO:18);
PLILLRLLRGQF(SEQ ID NO:19);
NAGSLLSGWG(SEQ ID NO:20);
NGVQPKY(SEQ ID NO:21);
DKYLPRPRPV(SEQ ID NO:22);
KFFKFFK(SEQ ID NO:23);
KFFK(SEQ ID NO:24);
KFFKFFKFFK(SEQ ID NO:25);和
RLWVLWRR(SEQ ID NO:26)。
在一个实施方案中,所述载体肽另外包含用于促进与双环肽缀合的部分。这种缀合促进部分包括叠氮丙氨酸(Aza)残基或叠氮赖氨酸(K(N3))残基。
在一个实施方案中,所述Aza或K(N3)残基存在于所述载体肽的N-或C-末端。
在进一步的实施方案中,所述Aza或K(N3)残基存在于N-或C-末端残基,所述载体肽选自:
(SEQ ID NO:12)-Aza(在本文中称为BCY13182);
(SEQ ID NO:13)-Aza(在本文中称为BCY13665);
(SEQ ID NO:14)-Aza(在本文中称为BCY13425);
Aza-(SEQ ID NO:15)(在本文中称为BCY13426);
(SEQ ID NO:16)-Aza(在本文中称为BCY13186);
(SEQ ID NO:17)-Aza(在本文中称为BCY13181);
(SEQ ID NO:18)-Aza(在本文中称为BCY13183);
(SEQ ID NO:19)-K(N3)(在本文中称为BCY13090);
(SEQ ID NO:20)-K(N3)(在本文中称为BCY13093);
(SEQ ID NO:21)-K(N3)(在本文中称为BCY13092);
(SEQ ID NO:22)-K(N3)(在本文中称为BCY13091);
(SEQ ID NO:23)-Aza(在本文中称为BCY12905);
(SEQ ID NO:24)-Aza(在本文中称为BCY12904);
(SEQ ID NO:25)-K(N3)(在本文中称为BCY11609);和
(SEQ ID NO:26)-K(N3)(在本文中称为BCY11608)。
在更进一步的实施方案中,所述Aza或K(N3)残基存在于N-或C-末端残基,所述载体肽选自:
(SEQ ID NO:12)-Aza(在本文中称为BCY13182);
(SEQ ID NO:13)-Aza(在本文中称为BCY13665);
(SEQ ID NO:14)-Aza(在本文中称为BCY13425);和
Aza-(SEQ ID NO:15)(在本文中称为BCY13426)。
抗感染缀合物
在一个具体的实施方案中,所述双环肽配体连接至TATA支架并缀合至载体肽,并且包含如表1中所列的抗感染缀合物:
表1:本发明的抗感染缀合物
缀合物编号 | 双环肽编号 | 载体肽编号 |
BCY14405 | BCY14287 | BCY13182 |
BCY14369 | BCY13769 | BCY13182 |
BCY14368 | BCY14278 | BCY13182 |
BCY14367 | BCY14277 | BCY13182 |
BCY14366 | BCY14276 | BCY13182 |
BCY14364 | BCY14280 | BCY13182 |
BCY14363 | BCY14279 | BCY13182 |
BCY14041 | BCY13813 | BCY13665 |
BCY14038 | BCY13812 | BCY13425 |
BCY14037 | BCY13812 | BCY13665 |
BCY13702 | BCY12805 | BCY13665 |
BCY13588 | BCY13416 | BCY13182 |
BCY13587 | BCY13415 | BCY13182 |
BCY13586 | BCY13417 | BCY13182 |
BCY13585 | BCY12805 | BCY13425 |
BCY13584 | BCY12805 | BCY13426 |
BCY13246 | BCY12805 | BCY13182 |
BCY13245 | BCY12805 | BCY13186 |
BCY13244 | BCY12805 | BCY13181 |
BCY13241 | BCY12805 | BCY13183 |
BCY13240 | BCY12805 | BCY13090 |
BCY13239 | BCY12805 | BCY13093 |
BCY13238 | BCY12805 | BCY13092 |
BCY13237 | BCY12805 | BCY13091 |
BCY13198 | BCY12805 | BCY12905 |
BCY13197 | BCY12805 | BCY12904 |
BCY13146 | BCY12824 | BCY11609 |
BCY13145 | BCY12824 | BCY11608 |
BCY13115 | BCY12804 | BCY11609 |
BCY13114 | BCY12804 | BCY12905 |
BCY12915 | BCY12805 | BCY11609 |
BCY12912 | BCY12821 | BCY11609 |
BCY12907 | BCY12673 | BCY12905 |
BCY12906 | BCY12673 | BCY12904 |
BCY12758 | BCY12674 | BCY11608 |
BCY12757 | BCY12673 | BCY11609 |
BCY12756 | BCY12673 | BCY11608 |
BCY12755 | BCY12674 | BCY11608 |
令人惊讶地,缀合物内载体肽和双环肽的存在提供了协同安排,其中所述双环肽能够以亲和性结合至PBP蛋白(即PBP3或PBP3a),而所述载体肽允许进入细菌的细胞以提供更有效的微生物细胞杀伤活性,如本文展示的数据所证明的那样。当在野生型细菌中单独测试时,未缀合双环肽没有抗微生物活性,但当在具有受损外膜(高孔化(hyperporinated)细胞)的细菌中测试时,未缀合双环肽在野生型细菌中显示出与缀合肽相似的抗微生物活性。缀合细菌在野生型和高孔化细胞中显示出相似的活性水平。
在进一步的实施方案中,本发明的抗感染缀合物选自BCY13246、BCY13584、BCY13585和BCY13702。
在更进一步的实施方案中,本发明的抗感染缀合物选自BCY13246。表2中显示的结果表明该缀合物对野生型大肠杆菌菌株以及相关的肠杆菌科细菌具有活性。
除非另有定义,否则本文所用的所有技术和科学术语具有与本领域普通技术人员通常理解的相同含义,如肽化学、细胞培养和噬菌体展示、核酸化学和生物化学领域。分子生物学、遗传和生化方法使用了标准技术(参见Sambrook等人,Molecular Cloning:ALaboratory Manual,第3版,2001,Cold Spring Harbor Laboratory Press,Cold SpringHarbor,NY;Ausubel等人,Short Protocols in Molecular Biology(1999),第4版,JohnWiley&Sons,Inc.),其通过引用并入本文。
术语
编号
当提及本发明的肽内的氨基酸残基位置时,由于半胱氨酸残基(Ci、Cii和Ciii)不变而从编号中将其省略,因此,本发明的肽内的氨基酸残基的编号参照如下:
Ci-S1-F2-P3-K4-Cii-P5-W6-V7-E8-G9-Ciii(SEQ ID NO:1)。
为了该描述的目的,假定所有双环肽都与1,1',1”-(1,3,5-三嗪烷-1,3,5-三基)三丙-2-烯-1-酮(TATA)环化并产生三取代的结构。与TATA的环化发生在Ci、Cii和Ciii上。
分子形式
双环核心序列的N-或C-末端延伸区添加于序列的左侧或右侧,以连字符分隔。例如,N-末端的βAla-Sar10-Ala尾巴将表示为:
βAla-Sar10-A-(SEQ ID NO:X)。
反向肽序列
根据Nair等人(2003)J Immunol 170(3),1362-1373中的公开,设想本文公开的肽序列也将以其逆-反形式使用。例如,该序列逆转(即N-末端变为C-末端,反之亦然),其立体化学同样也逆转(即D-氨基酸变为L-氨基酸,反之亦然)。
肽配体
如本文所指的,肽配体是指与分子支架共价结合的肽。通常,这样的肽包含两个或更多个能够与支架形成共价键的反应性基团(即半胱氨酸残基),和在所述反应性基团之间对向存在的序列,所述序列因为当所述肽与所述支架结合时形成环而被称为环序列。在这种情况下,所述肽包含至少三个半胱氨酸残基(在本文中称为Ci、Cii和Ciii),并且在所述支架上形成至少两个环。
肽配体的优点
本发明的某些双环肽具有许多有利的性质,其使它们被认为是适合注射、吸入、经鼻、经眼、口服或局部施用的类药物分子。这样的有利的性质包括:
-物种交叉反应性。某些配体在来自不同细菌物种的PBP之间表现出交叉反应性,因此能够治疗由多种细菌物种引起的感染。其他配体可以对某些细菌物种的PBP具有高度特异性,其可以有利于治疗感染而不会对患者的有益菌群造成附带损害;
-蛋白酶稳定性。双环肽配体理想地应表现出对血浆蛋白酶、上皮(“膜锚定的”)蛋白酶、胃和肠蛋白酶、肺表面蛋白酶、细胞内蛋白酶等的稳定性。蛋白酶的稳定性应当在不同物种之间保持,使得可以在动物模型中开发双环先导候选物,并可以有把握地对人施用;
-理想的溶解度曲线。其是带电荷的和亲水的残基相对于疏水的残基和分子内/分子间氢键的比例的函数,其对于制剂和吸收目的很重要;
-在循环中最佳的血浆半衰期。取决于临床适应症和治疗方案,可能需要开发在急性疾病管理环境中短时间暴露的双环肽;或者开发在循环中保留增强的双环肽,其因此对于治疗更慢性的疾病状态是最佳的。导致理想的血浆半衰期的其他因素是持续暴露以实现最大治疗效率的要求,相对于由于持续暴露于试剂而伴随的毒理;和
-选择性。本发明的某些肽配体表现出对特定PBP同种型的选择性,并且本发明的某些其他肽配体可以抑制一种以上的PBP同种型。
药学上可接受的盐
将理解的是,盐形式在本发明的范围内,并且提及肽配体包括所述配体的盐形式。
本发明的盐可以由包含碱性或酸性部分的母体化合物合成,其通过常规化学方法如Pharmaceutical Salts:Properties,Selection,and Use,P.Heinrich Stahl(编辑),Camille G.Wermuth(编辑),ISBN:3-90639-026-8,精装,388页,2002年8月中所述的方法。通常地,可以通过使这些化合物的游离酸或碱形式与合适的碱或酸在水中或在有机溶剂中、或在两者的混合物中反应来制备这样的盐。
可以用很多种无机和有机酸形成酸加成盐(单盐或二盐)。酸加成盐的示例包括与酸形成的单盐或二盐,所述酸选自乙酸、2,2-二氯乙酸、己二酸、藻酸、抗坏血酸(例如L-抗坏血酸)、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、(+)樟脑、樟脑磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环己氨磺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基乙磺酸、甲酸、富马酸、半乳糖二酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡糖醛酸(例如D-葡糖醛酸)、谷氨酸(例如L-谷氨酸)、α-氧代戊二酸、乙醇酸、马尿酸、氢卤酸(例如氢溴酸、盐酸、氢碘酸)、羟基乙磺酸、乳酸(例如(+)-L-乳酸、(±)-DL-乳酸)、乳糖酸、马来酸、苹果酸、(-)-L-苹果酸、丙二酸、(±)-DL-扁桃酸、甲磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、扑酸、磷酸、丙酸、丙酮酸、L-焦谷氨酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、鞣酸、(+)-L-酒石酸、硫氰酸、对甲苯磺酸、十一碳烯酸和戊酸、以及酰化的氨基酸和阳离子交换树脂。
一组特别的盐由由以下形成的盐组成:乙酸、盐酸、氢碘酸、磷酸、硝酸、硫酸、柠檬酸、乳酸、琥珀酸、马来酸、苹果酸、羟基乙磺酸、富马酸、苯磺酸、甲苯磺酸、硫酸、甲磺酸(methanesulfonic,mesylate)、乙磺酸、萘磺酸、戊酸、丙酸、丁酸、丙二酸、葡糖醛酸和乳糖酸。一种特别的盐是盐酸盐。另一种特别的盐是乙酸盐。
如果化合物是阴离子的,或具有可以是阴离子的官能团(例如-COOH可以是-COO-),则可以与有机或无机碱形成盐,生成合适的阳离子。合适的无机阳离子的示例包括但不限于:碱金属离子如Li+、Na+和K+,碱土金属阳离子如Ca2+和Mg2+,和其他阳离子如Al3+或Zn+。合适的有机阳离子的示例包括但不限于铵离子(即NH4 +)和被取代的铵离子(例如NH3R+、NH2R2 +、NHR3 +和NR4 +)。一些合适的被取代的铵离子的示例是那些衍生自以下的:甲胺、乙胺、二乙胺、丙胺、二环己胺、三乙胺、丁胺、乙二胺、乙醇胺、二乙醇胺、哌嗪、苄胺、苯基苄胺、胆碱、葡甲胺和氨丁三醇、以及氨基酸如赖氨酸和精氨酸。常见的季铵离子的一个示例是N(CH3)4 +。
当本发明的肽包含胺官能团时,其可以例如根据技术人员众所周知的方法与烷基化剂反应而形成季铵盐。这样的季铵化合物在本发明的肽的范围内。
修饰衍生物
将理解的是,本文所定义的肽配体的修饰衍生物在本发明的范围内。此类合适的修饰衍生物的示例包含选自以下的一种或多种修饰:N-末端和/或C-末端修饰;用一个或多个非天然氨基酸残基替换一个或多个氨基酸残基(如用一个或多个电子等排的或等电子的氨基酸替换一个或多个极性氨基酸残基;用其他非天然电子等排的或等电子的氨基酸替换一个或多个非极性氨基酸残基);添加间隔基团;用一个或多个抗氧化氨基酸残基替换一个或多个对氧化敏感的氨基酸残基;用丙氨酸替换一个或多个氨基酸残基,用一个或多个D-氨基酸残基替换一个或多个L-氨基酸残基;双环肽配体中一个或多个酰胺键的N-烷基化;用替代键替换一个或多个肽键;肽骨架长度的修饰;用另一个化学基团取代一个或多个氨基酸残基的α-碳上的氢,用合适的胺、硫醇、羧酸和酚反应性试剂修饰氨基酸如半胱氨酸、赖氨酸、谷氨酸/天冬氨酸和酪氨酸)以官能化所述氨基酸,以及引入或替换引入适合于官能化的正交反应活性的氨基酸,例如带有叠氮基或炔基的氨基酸,其分别允许用带有炔基或叠氮基的部分进行官能化。
在一个实施方案中,修饰衍生物包含N-末端和/或C-末端修饰。在进一步的实施方案中,其中所述修饰衍生物包含使用合适的氨基反应性化学的N-末端修饰和/或使用合适的羧基反应性化学的C-末端修饰。在进一步的实施方案中,N-末端或C-末端修饰包括添加效应基团,所述效应基团包括但不限于细胞毒性剂、放射螯合剂或发色团。
在进一步的实施方案中,修饰衍生物包含N-末端修饰。在进一步的实施方案中,N-末端修饰包含N-末端乙酰基。在该实施方案中,在肽合成过程中,N-末端半胱氨酸基团(在本文中称为Ci的基团)被乙酸酐或其他合适的试剂封端,导致分子被N-末端乙酰化。该实施方案提供了去除氨基肽酶的潜在识别点的优点,并避免了所述双环肽降解的可能性。
在可选的实施方案中,N-末端修饰包括添加分子间隔基团,其促进效应基团的缀合和保持双环肽对其靶标的效力。
在进一步的实施方案中,修饰衍生物包含C-末端修饰。在进一步的实施方案中,C-末端修饰包含酰胺基。在该实施方案中,在肽合成过程中,C-末端半胱氨酸基团(在本文中称为Ciii的基团)被合成为酰胺,导致分子被C-末端酰胺化。该实施方案提供了去除羧肽酶的潜在识别点的优点,并降低了所述双环肽的蛋白水解降解的可能性。
在一个实施方案中,修饰衍生物包含用一个或多个非天然氨基酸残基替换一个或多个氨基酸残基。在该实施方案中,可以选择具有电子等排的/等电子的侧链的非天然氨基酸,其既不被降解蛋白酶识别,也不对靶标效力产生任何不利影响。
可选地,可以使用具有受约束的氨基酸侧链的非天然氨基酸,使得附近的肽键的蛋白水解在构象和空间上受到阻碍。特别地,其涉及脯氨酸类似物、大型侧链、Cα-二取代的衍生物(例如氨基异丁酸(Aib))和环氨基酸,一个简单的衍生物是氨基-环丙基羧酸。
在一个实施方案中,修饰衍生物包含添加间隔基团。在进一步的实施方案中,修饰衍生物包含在N-末端半胱氨酸(Ci)和/或C-末端半胱氨酸(Ciii)上添加间隔基团。
在一个实施方案中,修饰衍生物包含用一个或多个抗氧化氨基酸残基替换一个或多个对氧化敏感的氨基酸残基。
在一个实施方案中,修饰衍生物包含用一个或多个疏水氨基酸残基替换一个或多个带电荷的氨基酸残基。在可选的实施方案中,修饰衍生物包含用一个或多个带电荷的氨基酸残基替换一个或多个疏水氨基酸残基。带电荷的与疏水的氨基酸残基的正确平衡是所述双环肽配体的重要特征。例如,疏水氨基酸残基影响血浆蛋白结合的程度,从而影响血浆中游离可利用部分的浓度,而带电荷的氨基酸残基(特别是精氨酸)可以影响所述肽与细胞表面磷脂膜的相互作用。两者组合起来可以影响所述肽药物的半衰期、分布容积和暴露,并且可以根据临床终点进行调整。另外,(如果所述肽药物已经皮下施用)带电荷的和疏水的氨基酸残基的正确组合和数量可以减少在注射部位的刺激。
在一个实施方案中,修饰衍生物包含用一个或多个D-氨基酸残基替换一个或多个L-氨基酸残基。该实施方案被认为通过空间位阻和通过D-氨基酸稳定β-转角构象的倾向来增加蛋白水解稳定性(Tugyi等人(2005)PNAS,102(2),413-418)。
在一个实施方案中,修饰衍生物包含去除任何氨基酸残基并用丙氨酸取代。该实施方案提供了去除潜在的蛋白水解进攻位点的优点。
应当指出的是,每个上述修饰用于有意地改善所述肽的效力或稳定性。通过修饰,可以通过以下机制进一步提高效力:
-并入利用疏水作用并导致较低的解离速率的疏水部分,使得实现更高的亲和力;
-并入利用长距离离子相互作用的带电基团,导致更快的结合速率和更高的亲和力(参见例如Schreiber等人,Rapid,electrostatically assisted association ofproteins(1996),Nature Struct.Biol.3,427-31);和
-将附加的约束并入肽中,例如通过正确地约束氨基酸的侧链使得在靶标结合时熵的损失最小,通过限制骨架的扭转角使得在靶标结合时熵的损失最小,和出于相同的原因在分子中引入另外的环化。
(综述见Gentilucci等人,Curr.Pharmaceutical Design(2010)16,3185-203和Nestor等人,Curr.Medicinal Chem(2009)16,4399-418)。
同位素变体
本发明包括所有药学上可接受的(放射性)同位素标记的本发明的肽配体,其中一个或多个原子被具有相同原子序数但原子质量或质量数不同于通常自然界中存在的原子质量或质量数的原子替换,和本发明的肽配体,其中连接金属螯合基团(称为“效应子”),其能够持有相关的(放射性)同位素,和本发明的肽配体,其中某些官能团被相关的(放射性)同位素或同位素标记的官能团共价取代。
适用于包含在本发明的肽配体中的同位素的示例包括氢同位素,如2H(D)和3H(T);碳同位素,如11C、13C和14C;氯同位素,如36Cl;氟同位素,如18F;碘同位素,如123I、125I和131I;氮同位素,如13N和15N;氧同位素,如15O、17O和18O;磷同位素,如32P;硫同位素,如35S;铜同位素,如64Cu;镓同位素,如67Ga或68Ga;钇同位素,如90Y;和镥同位素,如177Lu;和铋同位素,如213Bi。
某些同位素标记的本发明的肽配体,例如并入放射性同位素的那些,可用于药物和/或底物的组织分布研究。本发明的肽配体进一步可以具有有价值的诊断特性,其可用于检测或鉴定标记的化合物与其他分子、肽、蛋白质、酶或受体之间的复合物的形成。检测或鉴定方法可以使用用标记剂标记的化合物,如放射性同位素、酶、荧光物质、发光物质(例如鲁米诺、鲁米诺衍生物、荧光素、水母发光蛋白和荧光素酶)等。放射性同位素氚即3H(T)和碳-14即14C,由于其易于并入和现成的检测方法而对于这一目的特别有用。
用更重的同位素如氘即2H(D)取代,可以由于更大的代谢稳定性而提供某些治疗优势,例如增加的体内半衰期或减少的剂量要求,因此在某些情况下可能是优选的。
用正电子发射同位素如11C、18F、15O和13N取代,可以用于正电子发射成像(PET)研究以检查靶标占有率。
本发明的肽配体的同位素标记的化合物通常可以通过本领域技术人员已知的常规技术或通过与所附实施例中描述的那些方法类似的方法,使用合适的同位素标记的试剂代替之前采用的非标记的试剂来制备。
分子支架
在一个实施方案中,分子支架包括非芳香族分子支架。本文提及的“非芳香族分子支架”是指不包含芳香族(即不饱和)碳环或杂环系统的如本文所定义的任何分子支架。
非芳香族分子支架的合适示例描述于Heinis等人(2014),Angewandte Chemie,International Edition 53(6),1602-1606中。
如上述文档中所提及,分子支架可以是小分子,如有机小分子。
在一个实施方案中,所述分子支架可以是大分子。在一个实施方案中,所述分子支架是由氨基酸、核苷酸或碳水化合物组成的大分子。
在一个实施方案中,所述分子支架包含能够与多肽的官能团反应以形成共价键的反应性基团。
分子支架可以包含与肽形成连接的化学基团,如胺、硫醇、醇、酮、醛、腈、羧酸、酯、烯烃、炔烃、叠氮化物、酸酐、琥珀酰亚胺、马来酰亚胺、烷基卤和酰基卤。
含有αβ不饱和羰基的化合物的一个示例是1,1',1”-(1,3,5-三嗪烷-1,3,5-三基)三丙-2-烯-1-酮(TATA)(Angewandte Chemie International Edition(2014),53(6),1602-1606)。
合成
本发明的肽可以通过标准技术合成制造,然后与分子支架在体外反应。进行此操作时,可以使用标准化学方法。这使得能够快速大规模地制备可溶性材料,以用于进一步的下游实验或验证。可以使用如Timmerman等人(同上)中公开的常规化学方法来完成这样的方法。
因此,本发明还涉及如本文所述选择的多肽的制造,其中所述制造包括如下所述的任选的进一步的步骤。在一个实施方案中,这些步骤在通过化学合成制备的最终产物多肽上进行。
肽也可以延伸,以并入例如另一个环并因此引入多种特异性。
为了延伸所述肽,可以使用常规固相或溶液相化学方法,使用正交保护的赖氨酸(和类似物)简单地在其N-末端或C-末端或环内进行化学延伸。可以使用标准的(生物)缀合技术来引入激活的或可激活的N-或C-末端。可选地,可以通过片段缩合或天然化学连接进行添加,例如(Dawson等人,1994.Synthesis of Proteins by Native ChemicalLigation,Science 266:776-779)中描述的,或通过酶进行添加,例如使用如(Chang等人,Proc Natl Acad Sci U S A.1994年12月20日;91(26):12544-8或Hikari等人,Bioorganic&Medicinal Chemistry Letters Volume 18,Issue 22,2008年11月15日,6000-6003页)中描述的变位酶(subtiligase)。
可选地,可以通过二硫键的进一步缀合来延伸或修饰所述肽。这具有额外的优点,即允许第一和第二肽一旦在细胞的还原环境中即彼此解离。在这种情况下,可以在第一肽的化学合成过程中加入分子支架(例如TATA),以便与三个半胱氨酸基团反应;然后可以将进一步的半胱氨酸或硫醇附加到第一肽的N-或C-末端,使得该半胱氨酸或硫醇仅与第二肽的游离半胱氨酸或硫醇反应,形成二硫键连接的双环肽-肽缀合物。
类似的技术同样用于两个双环和双特异性大环的合成/偶联,潜在地产生四特异性分子。
此外,可以使用适当的化学方法,以相同的方式,在N-或C-末端或经由侧链偶联来添加其他官能团或效应子基团。在一个实施方案中,以不阻断任一实体个的活性的方式进行偶联。
药物组合物
根据本发明的一个进一步的方面,提供了一种药物组合物,其包含如本文所定义的肽配体,与一种或多种药学上可接受的赋形剂组合。
一般地,本发明的肽配体将以纯化形式与药理学上合适的赋形剂或载体(carrier)一起使用。通常,这些赋形剂或载体包括水性或醇/水溶液,乳液或悬浮液,包括盐水和/或缓冲介质。肠胃外载剂(vehicle)包括氯化钠溶液、林格氏葡萄糖、葡萄糖和氯化钠和乳酸林格氏液。如果需要使多肽复合物保持悬浮,则合适的生理学上可接受的佐剂可以选自增稠剂如羧甲基纤维素、聚乙烯吡咯烷酮、明胶和藻酸盐。
静脉内载剂包括液体和营养补充剂和电解质补充剂,如基于林格氏葡萄糖的那些。也可以存在防腐剂和其他添加剂,如抗微生物剂、抗氧化剂、螯合剂和惰性气体(Mack(1982),Remington's Pharmaceutical Sciences,第16版)。
本发明的化合物可以单独使用或与另一种或多种试剂组合使用。组合使用的另一种试剂可以是例如另一种抗生素,或抗生素“佐剂”,如用于提高革兰氏阴性菌渗透性的试剂、耐药决定子抑制剂或毒力机制抑制剂。
与本发明的化合物组合使用的合适的抗生素包括但不限于:
β内酰胺类,如青霉素类、头孢菌素类、碳青霉烯类或单环内酰胺类。合适的青霉素类包括苯唑西林、甲氧西林、氨苄西林、氯唑西林、羧苄西林、哌拉西林、替卡西林、氟氯西林和萘夫西林;合适的头孢菌素类包括头孢唑啉、头孢氨苄、头孢噻吩、头孢他啶、头孢吡肟、头孢吡普(ceftobiprole)、头孢洛林、头孢洛生(ceftolozane)和头孢地尔(cefiderocol);合适的碳青霉烯类包括美罗培南、多利培南、亚胺培南、厄他培南、比阿培南和泰比培南(tebipenem);合适的单环内酰胺类包括氨曲南;
林可胺类,如克林霉素和林可霉素;
大环内酯类,如阿奇霉素、克拉霉素、红霉素、泰利霉素(telithromycin)和索利霉素(solithromycin);
四环素类,如替加环素(tigecycline)、奥马环素(omadacycline)、依拉环素(eravacycline)、强力霉素和米诺环素;
喹诺酮类,如环丙沙星、左氧氟沙星、莫西沙星和德拉沙星(delafloxacin);
利福霉素类,如利福平、利福布汀、利福拉齐(rifalazil)、利福喷丁(rifapentine)和利福昔明(rifaximin);
氨基糖苷类,如庆大霉素、链霉素、妥布霉素、阿米卡星(amikacin)和普拉佐米星(plazomicin);
糖肽类,如万古霉素、替考拉宁(teichoplanin)、特拉万星(telavancin)、达巴万星(dalbavancin)和奥利万星(oritavancin);
截短侧耳素类(pleuromutilin),如来法莫林(lefamulin);
噁唑烷酮类,如利奈唑胺(linezolid)或特地唑胺(tedizolid);
多粘菌素类,如多粘菌素B或粘菌素;
甲氧苄氨嘧啶、艾拉普林(iclaprim)、磺胺甲噁唑;
甲硝唑;
非达霉素(fidaxomicin):
莫匹罗星(mupirocin);
夫西地酸;
达托霉素(daptomycin);
Murepavidin;
磷霉素;和
呋喃妥因(nitrofurantoin)。
合适的抗生素“佐剂”包括但不限于:
已知可改善细菌摄入的药物,如外膜透化剂或外排泵抑制剂;外膜透化剂可以包括多粘菌素B九肽或其他多粘菌素类似物,或依地酸钠;
耐药机制的抑制剂,如β-内酰胺酶抑制剂;合适的β-内酰胺酶抑制剂包括克拉维酸、他唑巴坦、舒巴坦、阿维巴坦(avibactam)、瑞来巴坦(relebactam)和那库巴坦(nacubactam);和
毒力机制(如毒素和分泌系统)的抑制剂,包括抗体。
本发明的化合物还可以与生物疗法组合使用,如基于核酸的疗法、抗体、噬菌体或噬菌体溶解酶。
根据本发明的药物组合物的施用途径可以是本领域普通技术人员通常已知的任何途径。为了治疗,可以根据标准技术将本发明的肽配体施用于任何患者。施用途径包括但不限于:口服(例如通过摄食);经颊;舌下;透皮(包括例如通过贴剂、膏药等);经粘膜(包括例如通过贴剂、膏药等);鼻内(例如通过鼻腔喷雾);经眼(例如通过滴眼液);经肺(例如通过吸入或吹入疗法,例如通过使用气雾剂,例如经口或鼻);经直肠(例如栓剂或灌肠剂);经阴道(例如通过阴道栓);肠胃外,例如通过注射,包括皮下、皮内、肌内、静脉内、动脉内、心内、鞘内、脊柱内、囊内、囊下、眶内、腹膜内、气管内、表皮下、关节内、蛛网膜下和胸骨下注射;通过植入贮库(depot)或储存器(reservoir),例如皮下或肌内植入。优选地,根据本发明的药物组合物将肠胃外施用。施用的剂量和频率将取决于患者的年龄、性别和状况、其他药物的同时施用、禁忌症和临床医生要考虑的其他参数。
可以将本发明的肽配体冻干用于储存,并在使用前在合适的载体中重构。已经表明该技术是有效的,并且可以采用本领域已知的冻干和重构技术。本领域技术人员将认识到,冻干和重构可以导致不同程度的活性损失,并且可能必须向上调节水平以进行补偿。
可以施用包含本发明的肽配体或其混合物的组合物以进行治疗性治疗。在某些治疗应用中,将足以完成选择的细胞群体的至少部分抑制(inhibition)、抑制(suppression)、调节、杀伤或一些其他可测量参数的量定义为“治疗有效剂量”。达到该剂量所需的量将取决于疾病的严重程度和患者自身免疫系统的一般状态,但一般为每千克体重10μg至250mg选择的肽配体,更常用的剂量为100μg至25mg/kg/剂量。
包含根据本发明的肽配体的组合物可以用于治疗环境中以治疗微生物感染或为有感染风险(例如正在接受手术、化学疗法、人工通气或其他病症或计划的干预)的受试者提供预防。另外,本文所述的肽配体可以在体外(extracorporeally)或体外(in vitro)选择性地用于从异质细胞集合中杀伤、消耗或以其他方式有效地去除靶细胞群体。可以将来自哺乳动物的血液与选择的肽配体在体外组合,从而将不期望的细胞杀伤或以其他方式从血液中去除,用于根据标准技术返回至哺乳动物。
治疗用途
本发明的双环肽作为PBP结合剂具有特殊的用途。
青霉素结合蛋白(PBP)是一组特征在于其对青霉素的亲和力和结合能力的蛋白质,它们存在于许多细菌物种中。所有的β-内酰胺类抗生素(除了抑制谷氨酰胺合成酶的tabtoxinine-β-内酰胺)均与细菌细胞壁合成所必需的PBP结合。PBP是称为转肽酶的酶亚组的成员。具体地,一些PBP是DD-转肽酶,而双功能PBP具有转糖基酶活性。PBP均参与肽聚糖合成的最后阶段,肽聚糖是细菌细胞壁的主要成分。细菌细胞壁合成对于细菌的生长、细胞分裂(从而繁殖)和维持细胞结构至关重要。抑制PBP导致细胞壁结构不规则,如伸长、损伤、丧失选择通透性以及最终细胞死亡和裂解。Macheboeuf等人,(2006)FEMSMicrobiology Reviews30(5),673-691提供了PBP的综述。
因此,不受理论的束缚,据信本发明的肽配体将能够通过与PBP结合和抑制细胞壁合成而引起细菌生长抑制、细胞死亡和裂解。Silver(2007)Nature Reviews DrugDiscovery 6,41-55和Zervosen等人(2012)Molecules 17(11),12478-12505提供了PBP作为治疗靶点的综述。将理解的是,本发明的肽配体可以在能够干扰所述PBP的作用机制的任何位点与PBP结合。例如,肽配体可以与所述PBP的活性位点结合并抑制转肽酶或转糖基酶。可选地,肽配体可以结合PBP上的其他位置以干扰其作用机制。
根据本发明的方法选择的多肽配体可以用于体内治疗应用、体外和体内诊断应用、体外试验和试剂应用等。在某些应用如疫苗应用中,可以利用对预定范围的抗原引起免疫反应的能力来调整疫苗适应特定的疾病和病原体。
对哺乳动物的施用优选具有至少90%至95%同质性的基本纯的肽配体,对于药物用途,特别是当所述哺乳动物是人时,最优选98%至99%或更高的同质性。选择的多肽一旦部分纯化或纯化至所期望的同质性,就可以用于诊断或治疗(包括体外)或用于开发和进行试验步骤、免疫荧光染色等(Lefkovite和Pernis(1979和1981),Immunological Methods,Volumes I and II,Academic Press,NY)。
根据本发明的进一步的方面,提供了如本文所定义的缀合物,其用于抑制或治疗细菌感染介导的疾病或疾患,或用于对有感染风险的受试者提供预防。
根据本发明的进一步的方面,提供了抑制或治疗细菌感染介导的疾病或疾患、或对有感染风险的受试者提供预防的方法,其包括向有需要的患者施用如本文所定义的缀合物。
本发明的缀合物或包含所述缀合物的药物组合物可用于治疗皮肤和软组织感染、胃肠道感染、尿路感染、肺炎、败血症、腹腔内感染和产科/妇科感染。所述感染可能由革兰氏阳性菌(如肺炎链球菌)或革兰氏阴性菌(如大肠杆菌、铜绿假单胞菌和鲍曼不动杆菌)引起,也可能由多于一种细菌物种引起。
在一个实施方案中,细菌感染介导的疾病或疾患选自:
·百日咳(可能由百日咳博德特氏菌引起);
·破伤风(可能由破伤风梭菌引起);
·白喉(可能由白喉棒状杆菌引起);
·棘球绦虫病(可能由棘球绦虫引起);
·腹泻、溶血性尿毒综合征或尿路感染(可能由大肠杆菌引起);
·呼吸道感染或脑膜炎(可能由流感嗜血杆菌引起);
·胃炎、消化性溃疡病或胃肿瘤(可能由幽门螺杆菌引起);
·结核病(可能由结核分枝杆菌引起);
·脑膜炎、肺炎、菌血症或中耳炎(可能由肺炎球菌引起);
·食物中毒(可能由沙门氏菌引起);
·志贺氏菌病或肠胃炎(可能由志贺氏菌引起);和
·霍乱(可能由霍乱弧菌引起)。
本文中提及的术语“抑制”是指在诱导事件之后但在疾病的临床表现之前施用组合物。“治疗”涉及在疾病症状变得明显之后施用保护性组合物。
已有可以用于筛选肽配体在预防或治疗疾病中的有效性的动物模型系统。
以下参考下列实施例进一步描述本发明。
实施例
材料和方法
肽的合成
肽的合成基于Fmoc化学,使用Peptide Instruments生产的Symphony肽合成仪和MultiSynTech生产的Syro II合成仪。使用标准的Fmoc-氨基酸(Sigma,Merck),其带有适当的侧链保护基团:在每种情况下均使用适用的标准偶联条件,然后使用标准方法进行脱保护。
可选地,使用HPLC纯化肽,并在分离后将其用1,3,5-三丙烯酰基六氢-1,3,5-三嗪(TATA,Sigma)修饰。为此,将线性肽用50:50MeCN:H2O稀释至约35mL,加入约500μL的100mMTATA的乙腈溶液,然后用5mL的1M NH4HCO3的H2O溶液引发反应。使反应在室温进行约30至60分钟,并且一旦反应完成即冻干(通过MALDI判断)。完成后,在室温将1mL的1M L-半胱氨酸盐酸盐一水合物(Sigma)的H2O溶液加入反应中约60分钟以淬灭任何过量的TATA。
冻干后,如上纯化修饰的肽,同时用Gemini C18柱(Phenomenex)替换Luna C8,并将酸改为0.1%三氟乙酸。合并包含正确的TATA修饰材料的纯级分,冻干并在-20℃进行保存。
除非另有说明,所有氨基酸均以L-构型使用。
在某些情况下,在使用以下方法与毒素的游离硫醇基偶联之前,先将肽转化为活化的二硫化物;将4-甲基(琥珀酰亚胺基4-(2-吡啶基硫代)戊酸酯)(100mM)在干燥DMSO(1.25mol当量)中的溶液加入肽(20mM)在干燥DMSO(1mol当量)中的溶液中。将反应充分混合并加入DIPEA(20mol当量)。通过LC/MS监测反应直至完成。
生物数据
最小抑制浓度(MIC)测定
使用以下大肠杆菌菌株:GKCW101;GKCW102和ATCC25922,使用AntimicrobialAgents and Chemotherapy 2016年12月第60卷12期:7372-7381页和CLSI,2020.Performance standards for antimicrobial susceptibility testing.ClinicalLab Standards Institute中描述的方法,进行最小抑制浓度(MIC)测定。结果示于表1中:
表1:选择的本发明的肽配体的MIC数据
nt=未测试
作为后续研究,测量了BCY13246针对一系列细菌靶标的MIC,并与单独的成分双环肽(BCY12130)和载体肽(BCY13182)以及现有的抗微生物剂美罗培南和左氧氟沙星的MIC进行了比较。结果示于表2中,其中可以看出缀合物BCY13246除了在相关肠杆菌科细菌中的活性外,还对野生型大肠杆菌菌株具有活性。缀合物的组成部分,即双环肽(BCY12130)和载体肽(BCY13182)没有显示出显著的活性,表明双环肽在不与载体缀合的情况下不能进入细胞,而载体没有抗微生物活性。
序列表
<110> 拜斯科技术开发有限公司
<120> 抗感染双环肽缀合物
<130> BIC-C-P2762PCT
<150> 2002705.8
<151> 2020-02-26
<160> 26
<170> PatentIn version 3.5
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Cys His Phe Pro Lys Cys Pro Trp Val Glu Gly Cys
1 5 10
<210> 7
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 7
Cys Lys Phe Pro Val Cys Pro Trp Val Glu Tyr Cys
1 5 10
<210> 8
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 8
Cys Val Tyr Pro Lys Cys Pro Trp Val Glu Gly Cys
1 5 10
<210> 9
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 9
Cys Arg Phe Pro Lys Cys Pro Trp Val Glu Gly Cys
1 5 10
<210> 10
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 10
Cys Ser Phe Pro Ala Cys Pro Trp Val Glu Gly Cys
1 5 10
<210> 11
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 11
Cys Phe Trp Gly Ser Cys Val Pro Glu Pro Lys Cys
1 5 10
<210> 12
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 12
Lys Ser Leu Arg Arg Val Trp Arg Ser Trp Arg
1 5 10
<210> 13
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 13
Lys Ser Leu Arg Arg Val Trp Arg Ser Trp Arg
1 5 10
<210> 14
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<220>
<221> Xaa
<222> (4)..(5)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (8)..(8)
<223> Xaa是HArg
<220>
<221> Xaa
<222> (11)..(11)
<223> Xaa是HArg
<400> 14
Lys Ser Leu Xaa Xaa Val Trp Xaa Ser Trp Xaa
1 5 10
<210> 15
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 15
Arg Trp Ser Arg Trp Val Arg Arg Leu Ser Lys
1 5 10
<210> 16
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 16
Val Lys Leu Phe Pro Val Lys Leu Phe Pro
1 5 10
<210> 17
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 17
Ser Leu Leu Ser Leu Ile Arg Lys Leu Ile Thr
1 5 10
<210> 18
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 18
Phe Phe Phe Leu Ser Arg Ile Phe Gly Lys
1 5 10
<210> 19
<211> 12
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 19
Pro Leu Ile Leu Leu Arg Leu Leu Arg Gly Gln Phe
1 5 10
<210> 20
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 20
Asn Ala Gly Ser Leu Leu Ser Gly Trp Gly
1 5 10
<210> 21
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 21
Asn Gly Val Gln Pro Lys Tyr
1 5
<210> 22
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 22
Asp Lys Tyr Leu Pro Arg Pro Arg Pro Val
1 5 10
<210> 23
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 23
Lys Phe Phe Lys Phe Phe Lys
1 5
<210> 24
<211> 4
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 24
Lys Phe Phe Lys
1
<210> 25
<211> 10
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 25
Lys Phe Phe Lys Phe Phe Lys Phe Phe Lys
1 5 10
<210> 26
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成肽
<400> 26
Arg Leu Trp Val Leu Trp Arg Arg
1 5
Claims (22)
1.一种抗感染肽缀合物,其包含:
(i)双环肽配体,其能够结合一个或多个青霉素结合蛋白(PBP),其包含多肽和分子支架,所述多肽包含被至少两个环序列隔开的至少三个半胱氨酸残基,并且所述分子支架与所述多肽的半胱氨酸残基形成共价键,使得在所述分子支架上形成至少两个多肽环;和
(ii)载体肽。
2.根据权利要求1所述的抗感染肽缀合物,其中所述环序列包含4或5个氨基酸。
3.根据权利要求1或2所述的抗感染肽缀合物,其中所述环序列包含被两个环序列隔开的三个半胱氨酸残基,所述两个环序列均由4个氨基酸组成。
4.根据权利要求1或2所述的抗感染肽缀合物,其中所述环序列包含被两个环序列隔开的三个半胱氨酸残基,所述两个环序列的一个由4个氨基酸组成,另一个由5个氨基酸组成。
5.根据权利要求1至4中任一项所述的抗感染肽缀合物,其中所述PBP是存在于一种或多种病原细菌物种内的PBP。
6.根据权利要求5所述的抗感染肽缀合物,其中所述一种或多种病原细菌物种选自以下任一项:鲍曼不动杆菌(Acinetobacter baumannii)、炭疽杆菌(Bacillus anthracis)、百日咳博德特氏菌(Bordetella pertussis)、伯氏疏螺旋体(Borrelia burgdorferi)、流产布鲁氏菌(Brucella abortus)、犬布鲁氏菌(Brucella canis)、马耳他布鲁氏菌(Brucella melitensis)、猪布鲁氏菌(Brucella suis)、空肠弯曲杆菌(Campylobacterjejuni)、肺炎衣原体(Chlamydia pneumonia)、沙眼衣原体(Chlamydia trachomatis)、鹦鹉热衣原体(Chlamydophila psittaci)、肉毒梭菌(Clostridium botulinum)、艰难梭菌(Clostridium difficile)、产气荚膜梭菌(Clostridium perfringens)、破伤风梭菌(Clostrium tetani)、白喉棒状杆菌(Corynebacterium diphtheriae)、棘球绦虫(Echinococcus)、粪肠球菌(Enterococcus faecalis)、屎肠球菌(Enterococcusfaecium)、大肠杆菌(Escherichia coli)(如产肠毒素大肠杆菌、肠致病性大肠杆菌、肠出血大肠杆菌或肠聚集性大肠杆菌)、土拉弗朗西斯菌(Francisella tularensis)、流感嗜血杆菌(Haemophilus influenzae)、幽门螺杆菌(Helicobacter pylori)、肺炎克雷伯菌(Klebsiella pneumoniae)、嗜肺军团菌(Legionella pneumophila)、问号钩端螺旋体(Leptospira interrogans)、单核细胞增生李斯特菌(Listeria monocytogenes)、麻风分枝杆菌(Mycobacterium leprae)、结核分枝杆菌(Mycobacterium tuberculosis)、溃疡分枝杆菌(Mycobacterium ulcerans)、肺炎支原体(Mycoplasma pneumonia)、淋病奈瑟菌(Neisseria gonorrhoeae)、脑膜炎奈瑟菌(Neisseria meningitides)、肺炎球菌(Pneumococcus)、铜绿假单胞菌(Pseudomonas aeruginosa)、立克次氏体(Rickettsiarickettsia)、沙门氏菌(如邦戈尔沙门氏菌(Salmonella bongori)、肠沙门氏菌(Salmonella enterica)、地下沙门氏菌(Salmonella subterranean)、伤寒沙门氏菌(Salmonella typhi)或鼠伤寒沙门氏菌(Salmonella typhimurium))、志贺氏菌(如索氏志贺氏菌(Shigella sonnei)或痢疾志贺氏菌(Shigella dysenteriae))、金黄色葡萄球菌(Staphylococcus aureus)(如MRSA)、表皮葡萄球菌(Staphylococcus epidermidis)、腐生葡萄球菌(Staphylococcus saprophyticus)、无乳链球菌(Streptococcus agalactiae)、肺炎链球菌(Streptococcus pneumoniae)、酿脓链球菌(Streptococcus pyogenes)、苍白密螺旋体(Treponema pallidum)、霍乱弧菌(Vibrio cholerae)或鼠疫耶尔森菌(Yersiniapestis)。
7.根据权利要求6所述的抗感染肽缀合物,其中所述PBP是大肠杆菌内存在的PBP3。
8.根据权利要求1至7中任一项所述的抗感染肽缀合物,其中所述PBP是大肠杆菌PBP3,所述双环肽配体包含选自以下的氨基酸序列:
CiSFPKCiiPWVEGCiii(SEQ ID NO:1);
CiRTFGCiiWWEGCiii(SEQ ID NO:2);
CiSFPKCiiPWVEGCiii(SEQ ID NO:3);
CiIYPKCiiPWVEGCiii(SEQ ID NO:4);
CiYFPKCiiPWVEGCiii(SEQ ID NO:5);
CiHFPKCiiPWVEGCiii(SEQ ID NO:6);
CiKFPVCiiPWVEYCiii(SEQ ID NO:7);
CiVYPKCiiPWVEGCiii(SEQ ID NO:8);
CiRFPKCiiPWVEGCiii(SEQ ID NO:9);
CiSFPACiiPWVEGCiii(SEQ ID NO:10);和
CiFWGSCiiVPEPKCiii(SEQ ID NO:11);
或其药学上可接受的盐,其中Ci、Cii和Ciii表示第一、第二和第三半胱氨酸残基,
如:
其中所述PBP是大肠杆菌PBP3,所述双环肽配体另外包含N-和/或C-末端添加,并且包含选自以下的氨基酸序列:
A-(SEQ ID NO:1)-A(在本文中称为BCY12130);
A-(SEQ ID NO:2)-A(在本文中称为BCY12132);
Ac-(SEQ ID NO:3)(在本文中称为BCY12742);
A-(SEQ ID NO:4)-A(在本文中称为BCY13769);
A-(SEQ ID NO:5)-A(在本文中称为BCY13756);
A-(SEQ ID NO:6)-A(在本文中称为BCY13754);
A-(SEQ ID NO:7)-A(在本文中称为BCY13747);
A-(SEQ ID NO:8)-A(在本文中称为BCY13768);
A-(SEQ ID NO:9)-A(在本文中称为BCY13766);
Ac-(SEQ ID NO:10)(在本文中称为BCY14682);和
A-(SEQ ID NO:11)-A(在本文中称为BCY14681);
或其药学上可接受的盐。
9.根据权利要求1至8中任一项所述的抗感染肽缀合物,其中所述双环肽配体另外包含用于促进与所述载体肽缀合的部分,如K(PYA)残基,其中PYA表示4-戊烯酸残基、或由6个乙二醇残基和末端叠氮基组成的连接基团(Peg6-叠氮化物)。
10.根据权利要求1至9中任一项所述的抗感染肽缀合物,其中所述双环肽配体另外包含在缀合促进部分和双环肽之间的间隔子,如多个肌氨酸(Sar)残基,即Sar5或Sar6。
11.根据权利要求1至10中任一项所述的抗感染肽缀合物,其中所述PBP是大肠杆菌PBP3,所述双环肽配体除了缀合促进部分和任选的间隔子之外另外包含N-和/或C-末端添加,并且包含选自以下的氨基酸序列:
A-(SEQ ID NO:1)-A-K(PYA)(在本文中称为BCY12805);
(PYA)G-Sar5)-A-(SEQ ID NO:1)-A-K(PYA)(在本文中称为BCY12821);
A-(SEQ ID NO:1)-A-Sar6-K(PYA)(在本文中称为BCY12673);
(PYA)K-A-(SEQ ID NO:1)-A(在本文中称为BCY13416);
(PYA)-A-(SEQ ID NO:1)-A(在本文中称为BCY12824);
A-(SEQ ID NO:2)-A-Sar6-K(PYA)(在本文中称为BCY12674);
Ac-(SEQ ID NO:3)-Lys4(Peg6-叠氮化物)(在本文中称为BCY14287);
Ac-(SEQ ID NO:3)-K(PYA)(在本文中称为BCY13812);
A-(SEQ ID NO:4)-A-K(PYA)(在本文中称为BCY14369);
A-(SEQ ID NO:5)-A-K(PYA)(在本文中称为BCY14278);
A-(SEQ ID NO:6)-A-K(PYA)(在本文中称为BCY14277);
A-(SEQ ID NO:7)-A-K(PYA)(在本文中称为BCY14276);
A-(SEQ ID NO:8)-A-K(PYA)(在本文中称为BCY14280);
A-(SEQ ID NO:9)-A-K(PYA)(在本文中称为BCY14279);
Ac-(SEQ ID NO:10)-K(PYA)(在本文中称为BCY13813);
(PYA)K-A-(SEQ ID NO:11)-A(在本文中称为BCY13415);
A-(SEQ ID NO:11)-A-K(PYA)(在本文中称为BCY13417);和
A-(SEQ ID NO:11)-A-Sar6-K(PYA)(在本文中称为BCY12804);
如:
A-(SEQ ID NO:1)-A-K(PYA)(在本文中称为BCY12805);
或其药学上可接受的盐。
12.根据权利要求1至11中任一项所述的抗感染肽缀合物,其中所述载体肽包含线性肽,如长度介于3和15个氨基酸之间、特别是介于4和12个氨基酸之间、更特别是4、7、8、10、11或12个氨基酸的线性肽。
13.根据权利要求1至12中任一项所述的抗感染肽缀合物,其中所述载体肽选自以下肽中的一种:
KSLRRVWRSWR(SEQ ID NO:12);
[dK][dS][dL][dR][dR][dV][dW][dR][dS][dW][dR](SEQ ID NO:13);
KSL[HArg][HArg]VW[HArg]SW[HArg](SEQ ID NO:14);
[dR][dW][dS][dR][dW][dV][dR][dR][dL][dS][dK](SEQ ID NO:15);
VKLFPVKLFP(SEQ ID NO:16);
SLLSLIRKLIT(SEQ ID NO:17);
FFFLSRIFGK(SEQ ID NO:18);
PLILLRLLRGQF(SEQ ID NO:19);
NAGSLLSGWG(SEQ ID NO:20);
NGVQPKY(SEQ ID NO:21);
DKYLPRPRPV(SEQ ID NO:22);
KFFKFFK(SEQ ID NO:23);
KFFK(SEQ ID NO:24);
KFFKFFKFFK(SEQ ID NO:25);和
RLWVLWRR(SEQ ID NO:26)。
14.根据权利要求1至13中任一项所述的抗感染肽缀合物,其中所述载体肽另外包含用于促进与双环肽缀合的部分,如叠氮丙氨酸(Aza)残基或叠氮赖氨酸(K(N3))残基。
15.根据权利要求14所述的抗感染肽缀合物,其中所述Aza或K(N3)残基存在于所述载体肽的N-或C-末端。
16.根据权利要求15所述的抗感染肽缀合物,其中所述Aza或K(N3)残基存在于N-或C-末端,所述载体肽选自:
(SEQ ID NO:12)-Aza(在本文中称为BCY13182);
(SEQ ID NO:13)-Aza(在本文中称为BCY13665);
(SEQ ID NO:14)-Aza(在本文中称为BCY13425);
Aza-(SEQ ID NO:15)(在本文中称为BCY13426);
(SEQ ID NO:16)-Aza(在本文中称为BCY13186);
(SEQ ID NO:17)-Aza(在本文中称为BCY13181);
(SEQ ID NO:18)-Aza(在本文中称为BCY13183);
(SEQ ID NO:19)-K(N3)(在本文中称为BCY13090);
(SEQ ID NO:20)-K(N3)(在本文中称为BCY13093);
(SEQ ID NO:21)-K(N3)(在本文中称为BCY13092);
(SEQ ID NO:22)-K(N3)(在本文中称为BCY13091);
(SEQ ID NO:23)-Aza(在本文中称为BCY12905);
(SEQ ID NO:24)-Aza(在本文中称为BCY12904);
(SEQ ID NO:25)-K(N3)(在本文中称为BCY11609);和
(SEQ ID NO:26)-K(N3)(在本文中称为BCY11608),
如:
(SEQ ID NO:12)-Aza(在本文中称为BCY13182);
(SEQ ID NO:13)-Aza(在本文中称为BCY13665);
(SEQ ID NO:14)-Aza(在本文中称为BCY13425);和
Aza-(SEQ ID NO:15)(在本文中称为BCY13426)。
17.根据权利要求1至16中任一项所述的抗感染肽缀合物,其选自:BCY14405、BCY14369、BCY14368、BCY14367、BCY14366、BCY14364、BCY14363、BCY14041、BCY14038、BCY14037、BCY13702、BCY13588、BCY13587、BCY13586、BCY13585、BCY13584、BCY13246、BCY13245、BCY13244、BCY13241、BCY13240、BCY13239、BCY13238、BCY13237、BCY13198、BCY13197、BCY13146、BCY13145、BCY13115、BCY13114、BCY12915、BCY12912、BCY12907、BCY12906、BCY12758、BCY12757、BCY12756和BCY12755,如BCY13246、BCY13584、BCY13585和BCY13702。
18.根据权利要求1至17中任一项所述的抗感染肽缀合物,其中所述分子支架是1,1',1”-(1,3,5-三嗪烷-1,3,5-三基)三丙-2-烯-1-酮(TATA)。
19.根据权利要求1至18中任一项所述的抗感染肽缀合物,其中所述药学上可接受的盐选自游离酸或钠、钾、钙和铵盐。
20.一种药物组合物,其包含根据权利要求1至19中任一项所述的抗感染肽缀合物,与一种或多种药学上可接受的赋形剂组合。
21.根据权利要求20所述的药物组合物,其另外包含一种或多种治疗剂。
22.根据权利要求1至19中任一项所定义的抗感染肽缀合物或如权利要求20或21所定义的药物组合物用于抑制或治疗细菌感染介导的疾病或疾患、或用于对有感染风险的受试者提供预防的用途。
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