Pharmacological Evaluation of Synthetic Dominant-Negative Peptides Derived from the Competence-Stimulating Peptide of Streptococcus pneumoniae.
Pharmacological Evaluation of Synthetic Dominant-Negative Peptides Derived from the Competence-Stimulating Peptide of Streptococcus pneumoniae.
复制标题
肺炎链球菌活性刺激肽合成的显性负肽的药理学评价。
DOI：
10.1021/acsptsci.2c00037
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发表时间：
2022
影响因子：
--
通讯作者：
Lau,GeeW
中科院分区：
文献类型：
--
作者：
Oh,MyungWhan;Lella,Muralikrishna;Kuo,ShannyHsuan;Tal-Gan,Yftah;Lau,GeeW
肺炎链球菌（肺炎球菌）的能力调控是一种群体感应回路，它调节这种病原体获得抗生素耐药性或进行血清型转换的能力，通过水平基因转移导致疫苗逃逸血清型，并启动毒力。能力调控的诱导主要是能力刺激肽（CSP）与其同源受体ComD的结合。我们最近合成了多种能够抑制能力诱导和毒力inS的显性阴性肽类似物。肺炎。然而，这些肽药物先导物的药效学和安全性还没有被描述。因此，在本研究中，我们使用IVIS光谱体内成像系统比较了花青氨酸-7.5标记的野生型CSPs与显性阴性肽类似物（dnCSPs）的生物稳定性。并对其体外毒性和体内毒性进行了评价。我们得出结论，我们最好的肽类似物CSP1-E1A-cyc（Dap6E10）是一种有吸引力的治疗肺炎球菌感染的药物，具有优越的安全性和药代动力学特征。
The competence regulon ofStreptococcus pneumoniae(pneumococcus) is a quorum-sensing circuitry that regulates the ability of this pathogen to acquire antibiotic resistance or perform serotype switching, leading to vaccine-escape serotypes, via horizontal gene transfer, as well as initiate virulence. Induction of the competence regulon is centered on binding of the competence-stimulating peptide (CSP) to its cognate receptor, ComD. We have recently synthesized multiple dominant-negative peptide analogs capable of inhibiting competence induction and virulence inS. pneumoniae. However, the pharmacodynamics and safety profiles of these peptide drug leads have not been characterized. Therefore, in this study, we compared the biostability of cyanine-7.5-labeled wild-type CSPs versus dominant-negative peptide analogs (dnCSPs) spatiotemporally by using an IVIS Spectrumin vivoimaging system. Moreover,in vitrocytotoxicity andin vivotoxicity were evaluated. We conclude that our best peptide analog, CSP1-E1A-cyc(Dap6E10), is an attractive therapeutic agent against pneumococcal infection with superior safety and pharmacokinetics profiles.