Buckheit R W, Lackman-Smith C, Snow M J, Halliday S M, White E L, Ross L J, Agrawal V K, Broom A D
Microbiology Research Department, Southern Research Institute, Frederick, MD 21701, USA.
Antivir Chem Chemother. 1999 Jan;10(1):23-32. doi: 10.1177/095632029901000103.
Poly(1-methyl-6-thioinosinic acid), or PMTI, is a single-stranded polyribonucleotide and is the first homopolyribonucleotide devoid of Watson-Crick hydrogen bonding sites to show potent human immunodeficiency virus (HIV) inhibition. PMTI was found to be active when evaluated against a variety of low passage clinical HIV isolates in fresh human peripheral blood cells, including T cell-tropic and monocyte-macrophage-tropic viruses, syncytium-inducing and non-syncytium-inducing viruses and viruses representative of the various HIV-1 clades (A through F). The compound was active against HIV-2, all nucleoside and non-nucleoside reverse transcriptase (RT) inhibitor drug-resistant virus isolates tested and interacted with AZT or ddl to synergistically inhibit HIV infection. In biochemical inhibition assays, PMTI was determined to be a potent inhibitor of HIV-1 and HIV-2 RT, including RTs with mutations that engender resistance to nucleoside and non-nucleoside RT inhibitors. PMTI inhibited both the polymerase and RNase H activities of HIV RT. PMTI did not inhibit HIV-1 protease or integrase. Cell-based mechanism of action assays indicated that PMTI also interfered with early events in the entry of HIV into target cells. Furthermore, PMTI inhibited the fusion of gp120-expressing and CD4-expressing cells, but at concentrations approximately 1 log10 greater than those that inhibited virus entry. These results suggest that the homopolyribonucleotide PMTI blocks HIV replication in human cells at its earliest stages by multiple mechanisms, inhibition of virus entry and inhibition of RT.
聚（1-甲基-6-硫代肌苷酸），即PMTI，是一种单链多聚核糖核苷酸，是首个不含沃森-克里克氢键位点却显示出强大的人类免疫缺陷病毒（HIV）抑制作用的同聚多核糖核苷酸。在新鲜人外周血细胞中针对多种低传代临床HIV分离株进行评估时，发现PMTI具有活性，这些分离株包括嗜T细胞和嗜单核细胞-巨噬细胞的病毒、合胞体诱导型和非合胞体诱导型病毒以及代表各种HIV-1进化枝（A至F）的病毒。该化合物对HIV-2、所有经测试的核苷和非核苷逆转录酶（RT）抑制剂耐药病毒分离株均有活性，并与齐多夫定（AZT）或双脱氧肌苷（ddl）相互作用以协同抑制HIV感染。在生化抑制试验中，PMTI被确定为HIV-1和HIV-2 RT的有效抑制剂，包括对核苷和非核苷RT抑制剂产生耐药性的突变RT。PMTI同时抑制HIV RT的聚合酶和核糖核酸酶H活性。PMTI不抑制HIV-1蛋白酶或整合酶。基于细胞的作用机制试验表明，PMTI还干扰HIV进入靶细胞的早期事件。此外，PMTI抑制表达gp120的细胞与表达CD4的细胞的融合，但所需浓度比抑制病毒进入的浓度大约高1个对数级。这些结果表明，同聚多核糖核苷酸PMTI通过多种机制在人类细胞中最早阶段阻断HIV复制，即抑制病毒进入和抑制RT。
