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Multistep optimization of a cell-penetrating peptide towards its antimicrobial activity
Biochemical Journal ( IF 4.4 ) Pub Date : 2021-01-15 , DOI: 10.1042/bcj20200698
Marco Drexelius 1 , Andre Reinhardt 1 , Joshua Grabeck 1 , Tom Cronenberg 2 , Frank Nitsche 3 , Pitter F. Huesgen 1, 4, 5 , Berenike Maier 2 , Ines Neundorf 1
Affiliation  

Multidrug resistant (MDR) bacteria have adapted to most clinical antibiotics and are a growing threat to human health. One promising type of candidates for the everlasting demand of new antibiotic compounds constitute antimicrobial peptides (AMPs). These peptides act against different types of microbes by permeabilizing pathogen cell membranes, whereas being harmless to mammalian cells. Contrarily, another class of membrane-active peptides, namely cell-penetrating peptides (CPPs), is known to translocate in eukaryotic cells without substantially affecting the cell membrane. Since CPPs and AMPs share several physicochemical characteristics, we hypothesized if we can rationally direct the activity of a CPP towards antimicrobial activity. Herein, we describe the screening of a synthetic library, based on the CPP sC18, including structure-based design to identify the active residues within a CPP sequence and to discover novel AMPs with high activity. Peptides with increased hydrophobicity were tested against various bacterial strains, and hits were further optimized leading to four generations of peptides, with the last also comprising fluorinated amino acid building blocks. Interestingly, beside strong antibacterial activities, we also detected activity in cancer cells, while non-cancerous cells remained unharmed. The results highlight our new candidates, particularly those from generation 4, as a valuable and promising source for the development of future therapeutics with antibacterial activity and beyond.

中文翻译:

细胞穿透肽针对其抗菌活性的多步优化

耐多药(MDR)细菌已经适应了大多数临床抗生素,并且对人类健康构成了越来越大的威胁。对新的抗生素化合物的持久需求的一种有希望的候选物类型是抗菌肽(AMPs)。这些肽通过透化病原体细胞膜而对不同类型的微生物起作用,而对哺乳动物细胞无害。相反,已知另一类膜活性肽,即细胞穿透肽(CPP),可在真核细胞中易位而基本不影响细胞膜。由于CPP和AMP具有一些理化特性,因此我们假设是否可以合理地将CPP的活性引向抗菌活性。在此,我们描述了基于CPP sC18的合成文库的筛选,包括基于结构的设计,以鉴定CPP序列中的活性残基并发现具有高活性的新型AMP。测试了具有增加的疏水性的肽对各种细菌菌株的影响,并进一步优化了命中结果,生成了四代肽,最后一种还包含氟化氨基酸构件。有趣的是,除了强大的抗菌活性外,我们还检测到了癌细胞中的活性,而非癌细胞则未受到损害。结果突显了我们的新候选人,特别是第四代的候选人,它们是开发具有抗菌活性及其他功能的未来疗法的宝贵和有希望的来源。测试了具有增加的疏水性的肽对各种细菌菌株的影响,并进一步优化了命中结果,生成了四代肽,最后一种还包含氟化氨基酸构件。有趣的是,除了强大的抗菌活性外,我们还检测到了癌细胞中的活性,而非癌细胞则未受到损害。结果突显了我们的新候选人,特别是第四代的候选人,它们是开发具有抗菌活性及其他功能的未来疗法的宝贵和有希望的来源。测试了具有增加的疏水性的肽对各种细菌菌株的影响,并进一步优化了命中结果,生成了四代肽,最后一种还包含氟化氨基酸构件。有趣的是,除了强大的抗菌活性外,我们还检测到了癌细胞中的活性,而非癌细胞则未受到损害。结果突出了我们的新候选药物,尤其是第四代的候选药物,它们是开发具有抗菌活性及其他功能的未来疗法的宝贵和有希望的来源。非癌细胞仍然没有受到伤害。结果突显了我们的新候选人,特别是第四代的候选人,它们是开发具有抗菌活性及其他功能的未来疗法的宝贵和有希望的来源。非癌细胞仍然没有受到伤害。结果突显了我们的新候选人,特别是第四代的候选人,它们是开发具有抗菌活性及其他功能的未来疗法的宝贵和有希望的来源。
更新日期:2021-01-08
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