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Dermaseptins as potential antirabies compounds

机译：Dermaseptins作为潜在的抗脂化合物

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Over the last 20 years, natural peptides playing a key role in defense mechanisms and innate immunity have been isolated from unicellular organisms. Amphibian skin secretes dermaseptins, 24-34 amino acids in length that have a wide antimicrobial spectrum incorporating yeast, fungi, protozoa, bacteria and enveloped viruses. The anti-rabies virus (RABV) activity of dermaseptins S3 (30aa) and S4 (28aa) from Phyllomedusa sauvagei has been investigated, and further dissected its molecular basis by comparing punctual mutation or deletion of S4 analogues. The results showed that: (1) S4 is more active than S3 against RABV infection, 89% versus 38% inhibition at 7.5 mu M; (2) the 5 NH2-aa of S4 are crucial for its inhibitory potential (S4(6-28) lost any inhibition) but the COOH terminus stabilizes the inhibitory potential (S4(1-16) showed only 23% inhibition at 7.5 mu M); (3) there is a correlation between viral inhibition and dermaseptin cytotoxicity, which remains however moderated for BSR cells (= 12% at 10 mu M). A single mutation in position 4 (S4(M4K)) slightly reduced cytotoxicity while keeping its antiviral activity, 97% at 7.5 mu M. S4 and S4(M4K )showed an antiviral activity in vitro when provided 1 h after infection. In vivo experiments in mice by intramuscular injection of non-toxic doses of dermaseptin S4(M4K) 1 h post-infection by a lethal dose of RABV at the same site allowed more than 50% improvement in mice survival. This study highlights the potential interest of dermaseptins as non-expansive alternatives to rabies immunoglobulins for the treatment of rabies that continues to claim about 60,000 human lives per year worldwide, almost exclusively in developing countries. (C) 2018 Elsevier Ltd. All rights reserved.
机译：在过去的20年中，在单细胞生物体中分离出防御机制和先天免疫力的自然肽。两栖动物皮肤分泌Dermaseptins，长度为24-34个氨基酸，具有较宽的抗微生物光谱，包含酵母，真菌，原生动物，细菌和包膜病毒。已经研究了从PhyllomedusaSauvagei的皮肽S3（30AA）和S4（28AA）的抗狂犬病病毒（RABV）活性，并通过比较分子突变或缺失S4类似物来进一步解释其分子基。结果表明：（1）S4比S3更活跃，针对RABV感染，89％对7.5μm的抑制作用; （2）S4的5 NH 2-AA对于其抑制电位至关重要（S4（6-28）丧失任何抑制），但COOH末端稳定抑制潜力（S4（1-16）显示在7.5亩的23％抑制m）; （3）病毒抑制与皮肽蛋白细胞毒性之间存在相关性，但对于BSR细胞（10μm，10μm）仍然适中。位置4的单一突变（S4（M4K））略微减少细胞毒性，同时保持其抗病毒活性，在感染后1小时时，在7.5μm，S4和S4（M4K）在7.5μm，S4和S4（M4K）中的97％。通过肌肉内注射无毒剂量的小鼠的小鼠体内实验，通过在同一部位的致死剂量的rabv后感染后感染允许的小鼠存活率超过50％。本研究突出了Dermaseptins作为狂犬病免疫球蛋白的非膨胀替代品的潜在兴趣，用于治疗狂犬病的狂犬病，该狂犬病的狂犬病仍在全球范围内持续索取约60,000名人类生命，几乎完全在发展中国家。 （c）2018年elestvier有限公司保留所有权利。

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