Preliminary Characterization of NP339, a Novel Polyarginine Peptide with Broad Antifungal Activity.
Preliminary Characterization of NP339, a Novel Polyarginine Peptide with Broad Antifungal Activity.
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DOI：
10.1128/aac.02345-20
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发表时间：
2021-07-16
影响因子：
4.9
通讯作者：
O'Neil D
中科院分区：
文献类型：
--
作者：
Duncan V;Smith D;Simpson L;Lovie E;Katvars L;Berge L;Robertson J;Smith S;Munro C;Mercer D;O'Neil D
真菌在全世界近十亿人中引起疾病。目前只有三类抗真菌药物可用于主流临床用途。新出现的耐药真菌、毒性和药物间相互作用损害了它们的疗效和适用性。因此，迫切需要新的和改进的抗真菌疗法。为了满足这一需求，我们开发了NP 339，这是一种2-kDa的聚精氨酸肽，其对来自念珠菌属、曲霉属和隐球菌属以及其他属的致病性真菌具有活性。NP 339是基于内源性阳离子人类防御肽设计的，其是针对病原微生物的免疫防御的基石的组成部分。NP 339通过电荷-电荷引发的膜相互作用特异性靶向真菌细胞膜，因此具有与现有抗真菌类别不同的安全性和毒性特征。NP 339是快速杀真菌的，并且在体外广泛传代后不会引起靶真菌的抗性。在鼠模型中的初步分析表明NP 339针对一系列全身性和皮肤粘膜真菌感染的治疗应用的范围。总的来说，这些数据表明，NP 339可以发展成为一种高度分化的，一流的抗真菌候选药物，用于治疗效果差的侵袭性和其他严重的真菌疾病。
Fungi cause disease in nearly one billion individuals worldwide. Only three classes of antifungal agents are currently available in mainstream clinical use. Emerging and drug-resistant fungi, toxicity, and drug-drug interactions compromise their efficacy and applicability. Consequently, new and improved antifungal therapies are urgently needed. In response to that need, we have developed NP339, a 2-kDa polyarginine peptide that is active against pathogenic fungi from the genera Candida, Aspergillus, and Cryptococcus, as well as others. NP339 was designed based on endogenous cationic human defense peptides, which are constituents of the cornerstone of immune defense against pathogenic microbes. NP339 specifically targets the fungal cell membrane through a charge-charge-initiated membrane interaction and therefore possesses a differentiated safety and toxicity profile to existing antifungal classes. NP339 is rapidly fungicidal and does not elicit resistance in target fungi upon extensive passaging in vitro. Preliminary analyses in murine models indicate scope for therapeutic application of NP339 against a range of systemic and mucocutaneous fungal infections. Collectively, these data indicate that NP339 can be developed into a highly differentiated, first-in-class antifungal candidate for poorly served invasive and other serious fungal diseases.