受Aureothin启发的新型合成聚酮化合物有效抑制HIV在原代人类细胞中的复制。,Scientific Reports

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受Aureothin启发的新型合成聚酮化合物有效抑制HIV在原代人类细胞中的复制。
Scientific Reports ( IF 3.8 ) Pub Date : 2020-01-28 , DOI: 10.1038/s41598-020-57843-9
Alexander Herrmann ₁ , Manfred Roesner ₂ , Thomas Werner ₃ , Stefanie M Hauck ₄ , Alisha Koch ₁ , Amelie Bauer ₁ , Martha Schneider ₁ , Ruth Brack-Werner ₁

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要克服艾滋病毒感染的全球健康威胁，就需要不断推出新的候选药物。通过对大量天然化合物的抗HIV筛选，我们确定了γ-吡喃酮聚酮类Aureothin / Neoaureothin是有效的药物。结构完整的金黄色素衍生物的全合成成功鉴定出优于金黄色素的前导化合物（＃7），该化合物具有较强的抗HIV活性（IC90 <45 nM），光稳定性和改善的细胞安全性。化合物＃7通过阻断编码病毒粒子结构成分并包括病毒基因组RNA的HIV RNA的积累，抑制了整合前病毒产生的新病毒。因此，化合物＃7表现出的作用方式不同于所有当前临床药物。蛋白质组学分析表明，化合物＃7不会影响原代血细胞中的整体蛋白表达，并且可能调节与HIV感染有关的细胞途径。化合物＃7与临床逆转录酶和整合酶抑制剂合用可抑制多种HIV基因型，包括1型和2型HIV，并协同抑制HIV。我们得出的结论是，化合物＃7代表了有希望的新型HIV抑制剂，它将有助于鉴定可用于抗病毒攻击的新病毒-宿主相互作用，并有望进一步开发药物。包括1型和2型HIV以及与临床逆转录酶和整合酶抑制剂合用的协同抑制型HIV。我们得出的结论是，化合物＃7代表了有希望的新型HIV抑制剂，它将有助于鉴定可用于抗病毒攻击的新病毒-宿主相互作用，并有望进一步开发药物。包括1型和2型HIV以及与临床逆转录酶和整合酶抑制剂合用的协同抑制型HIV。我们得出的结论是，化合物＃7代表了有希望的新型HIV抑制剂，它将有助于鉴定可用于抗病毒攻击的新病毒-宿主相互作用，并有望进一步开发药物。

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Potent inhibition of HIV replication in primary human cells by novel synthetic polyketides inspired by Aureothin.

Overcoming the global health threat of HIV infection requires continuous pipelines of novel drug candidates. We identified the γ-pyrone polyketides Aureothin/Neoaureothin as potent hits by anti-HIV screening of an extensive natural compound collection. Total synthesis of a structurally diverse group of Aureothin-derivatives successfully identified a lead compound (#7) superior to Aureothin that combines strong anti-HIV activity (IC90<45 nM), photostability and improved cell safety. Compound #7 inhibited de novo virus production from integrated proviruses by blocking the accumulation of HIV RNAs that encode the structural components of virions and include viral genomic RNAs. Thus, the mode-of-action displayed by compound #7 is different from those of all current clinical drugs. Proteomic analysis indicated that compound #7 does not affect global protein expression in primary blood cells and may modulate cellular pathways linked to HIV infection. Compound #7 inhibited multiple HIV genotypes, including HIV-type 1 and 2 and synergistically inhibited HIV in combination with clinical reverse transcriptase and integrase inhibitors. We conclude that compound #7 represents a promising new class of HIV inhibitors that will facilitate the identification of new virus-host interactions exploitable for antiviral attack and holds promise for further drug development.

更新日期：2020-01-29

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