Liu Jie, Wei Qiuyu, Liu Xin, Chen Jiang, Zhan Yujie, Li Qinglian, Wang Qian, Liang Bingyu, Jiang Junjun, Qin Fengxiang, Yuan Zongxiang, Qin Qiuzhen, Li Xuehua, Li Yangping, Liang Hao, Ye Li, Zhou Bo
Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning 530021, China.
Joint Laboratory for Emerging Infectious Diseases in China (Guangxi)-ASEAN, Life Sciences Institute, Guangxi Medical University, Nanning 530021, China.
Curr Issues Mol Biol. 2024 Nov 25;46(12):13482-13498. doi: 10.3390/cimb46120805.
The screening of novel antiviral agents from marine microorganisms is an important strategy for new drug development. Our previous study found that polyether K-41A and its analog K-41Am, derived from a marine Streptomyces strain, exhibit anti-HIV activity by suppressing the activities of HIV-1 reverse transcriptase (RT) and its integrase (IN). Among the K-41A derivatives, two disaccharide-bearing polyethers-K-41B and K-41Bm-were found to have potent anti-HIV-1 activity in vitro. This study aimed to clarify whether K-41B and K-41Bm have inhibitory effects on different HIV-1 strains or whether these two derivatives have mechanisms of action different from that of their precursor, K-41A. An anti-HIV-1 assay indicated that K-41B and K-41Bm have potent anti-HIV-1 activity, with low 50% inhibitory concentrations (ICs) (0.076 and 0.208 μM, respectively) and high selective indexes (SIs) (58.829 and 31.938, respectively) in the peripheral blood mononuclear cell (PBMC)-HIV-1 system. The time-of-addition (TOA) assay indicated that K-41B and K-41Bm may exert antiviral effects by activating multiple stages of HIV-1 replication. A cell protection assay indicated that the pretreatment of cells with K-41B or K-41Bm has almost no inhibitory effect on HIV-1 infection. A virus inactivation assay indicated that pretreatment of the virus with K-41B or K-41Bm inhibits HIV-1 infection by 60%. A cell-cell fusion assay showed that K-41B and K-41Bm blocked the cell fusion mediated by viral envelope proteins. The HIV-1 key enzyme experiment also indicated that both compounds have certain inhibitory effects on HIV-1 IN. Furthermore, molecular docking showed that K-41B and K-41Bm interact with several viral and host proteins, including HIV-1 IN, an envelope protein (gp120), a transmembrane protein (gp41), and cell surface receptors (CD4, CCR5, and CXCR4). Overall, in addition to having a similar anti-HIV-1 mechanism of inhibiting HIV-1 IN like the precursor polyether K-41A, the disaccharide-bearing polyether derivatives K-41B and K-41Bm may also inhibit viral entry. This suggests that they display anti-HIV-1 mechanisms that are different from those of their precursor polyethers.
从海洋微生物中筛选新型抗病毒药物是新药研发的重要策略。我们之前的研究发现，从一株海洋链霉菌中分离得到的聚醚K - 41A及其类似物K - 41Am，通过抑制HIV - 1逆转录酶（RT）及其整合酶（IN）的活性来展现抗HIV活性。在K - 41A衍生物中，两种带有二糖的聚醚——K - 41B和K - 41Bm——在体外被发现具有强大的抗HIV - 1活性。本研究旨在阐明K - 41B和K - 41Bm是否对不同的HIV - 1毒株有抑制作用，或者这两种衍生物是否具有与其前体K - 41A不同的作用机制。一项抗HIV - 1试验表明，在人外周血单个核细胞（PBMC）-HIV - 1系统中，K - 41B和K - 41Bm具有强大的抗HIV - 1活性，其50%抑制浓度（IC）较低（分别为0.076和0.208 μM），选择性指数（SI）较高（分别为58.829和31.938）。加样时间（TOA）试验表明，K - 41B和K - 41Bm可能通过激活HIV - 1复制的多个阶段发挥抗病毒作用。细胞保护试验表明，用K - 41B或K - 41Bm预处理细胞对HIV - 1感染几乎没有抑制作用。病毒灭活试验表明，用K - 41B或K - 41Bm预处理病毒可使HIV - 1感染降低60%。细胞 - 细胞融合试验表明，K - 41B和K - 41Bm可阻断病毒包膜蛋白介导的细胞融合。HIV - 1关键酶实验也表明，这两种化合物对HIV - 1 IN均有一定的抑制作用。此外，分子对接显示，K - 41B和K - 41Bm与多种病毒和宿主蛋白相互作用，包括HIV - 1 IN、一种包膜蛋白（gp120）、一种跨膜蛋白（gp41）以及细胞表面受体（CD4、CCR5和CXCR4）。总体而言，除了具有与前体聚醚K - 41A类似的抑制HIV - 1 IN的抗HIV - 1机制外，带有二糖的聚醚衍生物K - 41B和K - 41Bm还可能抑制病毒进入。这表明它们展现出与前体聚醚不同的抗HIV - 1机制。
