A series of novel water-soluble short peptide-bioconjugates containing a ferrocenoyl (Fc) or ruthenocenoyl (Rc) unit was synthesized and characterized to combine the unique activity of ferrocene and the isoelectronic ruthenocene with precisely designed peptide structures. We aim at evaluating these bioconjugates as a new class of OrganoMetallic Short AntiMicrobial Peptides (OM-SAMPs). The series of OM-SAMPs was designed with a set of linear and “head-to-tail” cyclic metallocene-based hexapeptides derived from the homo-sequence H-KKKKKK-NH₂ by substitution of lysine (K) by tryptophan (W) and by orthogonal derivatization of the ε-N-amine group of lysine by a metallocene moiety. Peptide conjugates were characterized by RP-HPLC, mass spectrometry (ESI and MALDI-TOF) and circular dichroism (CD) spectroscopy. Gram-positive and Gram-negative antibacterial activity testings were carried out to explore the role of insertion of the metallocene fragment into the peptide, and the effect of the modification of the cationic charge and aromatic residues on the physiochemical properties of these OM-SAMPs. These results show that the insertion of two tryptophan residues and ferrocenoyl/ruthenocenoyl moieties into a linear homo-sequence peptides increase significantly their antibacterial activity with minimum inhibitory concentration values as low as 5 μM for the most active compounds. However, “head-to-tail” cyclic metallocene-based hexapeptides were not active against Gram-negative bacteria up to concentrations of 50 μM. These studies provide a better understanding of the role of structural modifications to enhance antibacterial peptide activity, which is promising for their therapeutic application.

Graphic abstract

中文翻译：

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作为潜在抗菌化合物的线性和环状二茂铁酰基/芸香烯酰基水溶性六肽的固相合成和评价

合成并表征了一系列含有二茂铁酰基 (Fc) 或 ruthenocenoyl (Rc) 单元的新型水溶性短肽-生物共轭物，以将二茂铁和等电子 ruthenocene 的独特活性与精确设计的肽结构相结合。我们的目标是评价这些生物缀合物作为一类新的ö rgano中号etallic小号园艺甲NTI中号icrobial P eptides（OM-SAMPS）。该系列 OM-SAMP 设计了一组线性和“头对尾”环状茂金属基六肽，这些六肽来源于同源序列 H-KKKKKK-NH ₂通过用色氨酸 (W) 取代赖氨酸 (K) 和通过茂金属部分对赖氨酸的 ε- N-胺基进行正交衍生。肽缀合物通过 RP-HPLC、质谱（ESI 和 MALDI-TOF）和圆二色性 (CD) 光谱表征。进行革兰氏阳性和革兰氏阴性抗菌活性测试，以探索茂金属片段插入肽的作用，以及阳离子电荷和芳香族残基的修饰对这些 OM-SAMP 理化性质的影响。这些结果表明，将两个色氨酸残基和二茂铁酰基/二茂铁烯酰基部分插入线性同源-序列肽显着提高了它们的抗菌活性，对于活性最强的化合物，其最小抑菌浓度值低至 5 μM。然而，“头对尾”环状茂金属六肽在浓度高达 50 μM 时对革兰氏阴性菌没有活性。这些研究提供了对结构修饰在增强抗菌肽活性方面的作用的更好理解，这对其治疗应用很有希望。

图形摘要