PDF(Pubmed)
Abstract：
In this work, we sought to develop a TP4-based stapled peptide that can be used to counter polymicrobial sepsis. First, we segregated the TP4 sequence into hydrophobic and cationic/hydrophilic zones and substituted the preferred residue, lysine, as the sole cationic amino acid. These modifications minimized the intensity of cationic or hydrophobic characteristics within small segments. Then, we incorporated single or multiple staples into the peptide chain, bracketing the cationic/hydrophilic segments to improve pharmacological suitability. Using this approach, we were able to develop an AMP with low toxicity and notable in vivo efficacy. IMPORTANCE In our in vitro studies, one dual stapled peptide out of the series of candidates (TP4-3: FIIXKKSXGLFKKKAGAXKKKXIKK) showed significant activity, low toxicity, and high stability (in 50% human serum). When tested in cecal ligation and puncture (CLP) mouse models of polymicrobial sepsis, TP4-3 improved survival (87.5% on day 7). Furthermore, TP4-3 enhanced the activity of meropenem against polymicrobial sepsis (100% survival on day 7) compared to meropenem alone (37.5% survival on day 7). Molecules such as TP4-3 may be well suited for a wide variety of clinical applications.
摘要：
在这项工作中,我们寻求开发一种基于TP4的钉合肽,可用于对抗多微生物败血症.首先,我们将TP4序列分离为疏水和阳离子/亲水区，并取代了优选的残基，赖氨酸，作为唯一的阳离子氨基酸。这些修饰使小段内的阳离子或疏水特性的强度最小化。然后，我们在肽链中加入了单个或多个主食，将阳离子/亲水链段包围以提高药理学适用性。使用这种方法，我们能够开发出低毒性和显著体内疗效的AMP。重要性在我们的体外研究中，候选物系列中的一个双重钉合肽(TP4-3:FIXKKSXGLFKKKKAGAXKKKXIKK)显示出显著的活性,低毒性,和高稳定性（在50％的人血清）。当在盲肠结扎和穿孔（CLP）多微生物败血症小鼠模型中进行测试时，TP4-3提高了存活率(第7天87.5%)。此外，与单独的美罗培南(第7天37.5%存活率)相比,TP4-3增强了美罗培南对抗多微生物败血症的活性(第7天100%存活率)。诸如TP4-3的分子可以很好地适用于多种临床应用。
