Rega Institute for Medical Research, Leuven, Belgium.
Curr Top Microbiol Immunol. 2013;369:289-320. doi: 10.1007/978-3-642-27340-7_12.
The major targets for direct-acting antivirals (DAAs) are the NS3/4A protease, the NS5A protein, and the NS5B polymerase. The latter enzyme offers several target sites: the catalytic domain for nucleoside/nucleotide analogs and different allosteric sites for non-nucleoside inhibitors. Two protease inhibitors have already been approved and more than 40 new NS3/4A, NS5A, or NS5B inhibitors are in development pipeline. Not only these agents can achieve very high cure rates when combined with PEG-IFN and RBV, but have also started to provide promising results when combined in IFN-free, all-oral combinations. In addition to the more canonical drug targets, new alternative viral targets for small molecule drug development are emerging, such as p7 or NS4B. Current research is focusing on defining the most efficacious DAA combination regimens, i.e., those which provide the highest rates of viral eradication, broadest spectrum of action, minimal or no clinical resistance, shortest treatment duration, and good tolerability.
直接作用抗病毒药物 (DAAs) 的主要靶点是 NS3/4A 蛋白酶、NS5A 蛋白和 NS5B 聚合酶。后一种酶有几个靶位：核苷/核苷酸类似物的催化结构域和非核苷抑制剂的不同变构位点。已有两种蛋白酶抑制剂获得批准，超过 40 种新的 NS3/4A、NS5A 或 NS5B 抑制剂正在研发中。这些药物不仅与 PEG-IFN 和 RBV 联合使用时可达到非常高的治愈率，而且在无干扰素、全口服联合治疗中也开始取得有前景的结果。除了更典型的药物靶点外，小分子药物开发的新的替代病毒靶点也在不断涌现，如 p7 或 NS4B。目前的研究重点是确定最有效的 DAA 联合治疗方案，即提供最高病毒清除率、最广泛作用谱、最小或无临床耐药性、最短治疗持续时间和良好耐受性的方案。
