Architecture et Réactivité de l'ARN, Université de Strasbourg, CNRS, IBMC, France.
J Med Chem. 2010 Feb 25;53(4):1534-45. doi: 10.1021/jm901758f.
With the goal of limiting HIV-1 proliferation by increasing the mutation rate of the viral genome, we synthesized a series of pyrimidine nucleoside analogues modified in position 5 of the aglycone moiety but unmodified on the sugar part. The synthetic strategies allow us to prepare the targeted compounds directly from commercially available nucleosides. All compounds were tested for their ability to reduce HIV-1 proliferation in cell culture. Two of them (5-hydroxymethyl-2'-dU (1c) and 5-hydroxymethyl-2'-dC (2c)) displayed a moderate antiviral activity in single passage experiments. The same two compounds plus two additional ones (5-carbamoyl-2'-dU (1a) and 5-carbamoylmethyl-2'-dU (1b)) were potent inhibitors of HIV-1 RT activity in serial passage assays, in which they induced a progressive loss of HIV-1 replication. In addition, viruses collected after seven passages in the presence of 1c and 2c replicated very poorly after withdrawal of these compounds, consistent with the accumulation of deleterious mutations in the HIV-1 genome.
我们合成了一系列嘧啶核苷类似物，这些类似物在糖苷部分的位置 5 上修饰，但在糖部分未修饰，目的是通过增加病毒基因组的突变率来限制 HIV-1 的增殖。合成策略使我们能够直接从商业可得的核苷制备目标化合物。所有化合物均在细胞培养中测试其抑制 HIV-1 增殖的能力。其中两种化合物（5-羟甲基-2'-dU（1c）和 5-羟甲基-2'-dC（2c））在单次传代实验中显示出中等的抗病毒活性。相同的两种化合物加上另外两种化合物（5-氨甲酰基-2'-dU（1a）和 5-氨甲酰基甲基-2'-dU（1b））在连续传代测定中是 HIV-1 RT 活性的有效抑制剂，它们诱导 HIV-1 复制的逐渐丧失。此外，在存在 1c 和 2c 的情况下经过七次传代收集的病毒在这些化合物被撤去后复制能力非常差，这与 HIV-1 基因组中积累有害突变一致。
