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抗感染及抗炎肽Pep19-2.5的毒理学和安全药理学分析

Toxicological and Safety Pharmacological Profiling of the Anti-Infective and Anti-Inflammatory Peptide Pep19-2.5.

作者信息

Möller Clemens, Heinbockel Lena, Garidel Patrick, Gutsmann Thomas, Mauss Karl, Weindl Günther, Fukuoka Satoshi, Loser Dominik, Danker Timm, Brandenburg Klaus

机构信息

Life Sciences Faculty, Albstadt-Sigmaringen University, 72488 Sigmaringen, Germany.

Brandenburg Antiinfektiva GmbH, c/o Forschungszentrum Borstel, 23845 Borstel, Germany.

出版信息

Microorganisms. 2022 Dec 6;10(12):2412. doi: 10.3390/microorganisms10122412.

DOI:10.3390/microorganisms10122412
PMID:36557665
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9782211/
Abstract

Aspidasept (Pep19-2.5) and its derivative Pep19-4LF ("Aspidasept II") are anti-infective and anti-inflammatory synthetic polypeptides currently in development for application against a variety of moderate to severe bacterial infections that could lead to systemic inflammation, as in the case of severe sepsis and septic shock, as well as application to non-systemic diseases in the case of skin and soft tissue infections (SSTI). In the present study, Aspidasept and Aspidasept II and their part structures were analysed with respect to their toxic behavior in different established models against a variety of relevant cells, and in electrophysiological experiments targeting the hERG channel according to ICH S7B. Furthermore, the effects in mouse models of neurobiological behavior and the local lymph node according to OECD test guideline 429 were investigated, as well as a rat model of repeated dose toxicology according to ICH M3. The data provide conclusive information about potential toxic effects, thus specifying a therapeutic window for the application of the peptides. Therefore, these data allow us to define Aspidasept concentrations for their use in clinical studies as parenteral application.

摘要

天冬酰胺肽（Pep19 - 2.5）及其衍生物Pep19 - 4LF（“天冬酰胺肽II”）是目前正在研发的抗感染和抗炎合成多肽，用于治疗多种可能导致全身炎症的中度至重度细菌感染，如严重脓毒症和脓毒性休克，以及用于皮肤和软组织感染（SSTI）等非全身性疾病。在本研究中，针对天冬酰胺肽和天冬酰胺肽II及其部分结构，在不同的既定模型中对多种相关细胞进行了毒性行为分析，并根据ICH S7B针对hERG通道进行了电生理实验。此外，根据经合组织测试指南429研究了其在小鼠神经生物学行为模型和局部淋巴结中的作用，以及根据ICH M3进行了大鼠重复剂量毒理学模型研究。这些数据提供了有关潜在毒性作用的确凿信息，从而明确了这些多肽应用的治疗窗口。因此，这些数据使我们能够确定天冬酰胺肽用于临床研究（肠胃外应用）的浓度。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/5be5fbd6bc47/microorganisms-10-02412-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/2e49829f72f6/microorganisms-10-02412-sch001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/ef72172e4045/microorganisms-10-02412-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/c8344485e054/microorganisms-10-02412-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/f442e184edb3/microorganisms-10-02412-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/ac03f98bbb5e/microorganisms-10-02412-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/62b487db11a3/microorganisms-10-02412-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/59a32f956e78/microorganisms-10-02412-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/4b56f479eea0/microorganisms-10-02412-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/8af6d9d60682/microorganisms-10-02412-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/dfe098c414bc/microorganisms-10-02412-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/5be5fbd6bc47/microorganisms-10-02412-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/2e49829f72f6/microorganisms-10-02412-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/630680eedfb6/microorganisms-10-02412-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/ef72172e4045/microorganisms-10-02412-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/c8344485e054/microorganisms-10-02412-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/f442e184edb3/microorganisms-10-02412-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/ac03f98bbb5e/microorganisms-10-02412-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/62b487db11a3/microorganisms-10-02412-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/59a32f956e78/microorganisms-10-02412-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/4b56f479eea0/microorganisms-10-02412-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/8af6d9d60682/microorganisms-10-02412-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/dfe098c414bc/microorganisms-10-02412-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fac0/9782211/5be5fbd6bc47/microorganisms-10-02412-g010.jpg

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Synthetic anti-endotoxin peptides inhibit cytoplasmic LPS-mediated responses.合成抗内毒素肽抑制细胞质 LPS 介导的反应。
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Synthetic antimicrobial and LPS-neutralising peptides suppress inflammatory and immune responses in skin cells and promote keratinocyte migration.合成抗菌肽和 LPS 中和肽可抑制皮肤细胞的炎症和免疫反应，并促进角质形成细胞迁移。
Sci Rep. 2016 Aug 11;6:31577. doi: 10.1038/srep31577.
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The Changing Epidemiology and Definitions of Sepsis.脓毒症不断变化的流行病学及定义
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The Synthetic Antimicrobial Peptide 19-2.5 Interacts with Heparanase and Heparan Sulfate in Murine and Human Sepsis.合成抗菌肽19-2.5在小鼠和人类脓毒症中与乙酰肝素酶和硫酸乙酰肝素相互作用。
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