Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Laboratório de Bioquı́mica de Peptı́deos, Universidade Federal de São Paulo, 12231-280 São José dos Campos, Brazil.
J Med Chem. 2020 Sep 10;63(17):9391-9402. doi: 10.1021/acs.jmedchem.0c00543. Epub 2020 Aug 31.
Available treatments for invasive fungal infections have limitations, including toxicity and the emergence of resistant strains. Therefore, there is an urgent need for alternative solutions. Because of their unique mode of action and high selectivity, plant defensins (PDs) are worthy therapeutic candidates. Chemical synthesis remains a preferred method for the production of many peptide-based therapeutics. Given the relatively long sequence of PDs, as well as their complicated posttranslational modifications, the synthetic route can be considered challenging. Here, we describe a total synthesis of D, the defensin from the common bean . Analytical, structural, and functional characterization revealed that both natural and synthetic peptides fold into a canonical CSαβ motif stabilized by conserved disulfide bonds. Moreover, synthetic D retained the biological activity against four different species and showed no toxicity . Adding the high resistance of synthetic D to proteolytic degradation, we claim that conditions are now met to consider PDs druggable biologicals.
现有治疗侵袭性真菌感染的方法存在局限性，包括毒性和耐药菌株的出现。因此，迫切需要替代解决方案。由于植物防御素（PDs）具有独特的作用模式和高度的选择性，因此它们是很有前途的治疗候选物。化学合成仍然是许多基于肽的治疗药物的首选生产方法。鉴于 PDs 的相对较长序列以及其复杂的翻译后修饰，合成路线可能具有挑战性。在这里，我们描述了来自普通菜豆的防御素 D 的全合成。分析、结构和功能表征表明，天然和合成肽都折叠成一个由保守的二硫键稳定的典型 CSαβ 基序。此外，合成的 D 保留了对四种不同真菌物种的生物活性，并且没有毒性。由于合成 D 对蛋白水解降解具有高度抗性，我们认为现在的条件已经满足，可以考虑将 PDs 作为可药用的生物制剂。
