de Soultrait V Richard, Desjobert C, Tarrago-Litvak L
REGER Laboratory, UMR 5097 CNRS-Université Victor Segalen, Bordeaux 2, France.
Curr Med Chem. 2003 Sep;10(18):1765-78. doi: 10.2174/0929867033457007.
Current treatments of human immunodeficiency virus type 1 (HIV-1) infection consist in the combination of drugs targeting reverse transcriptase (RT) and protease (PR). Despite the multiple clinical benefits of this combination therapy, the emergence of resistance highlights the need for new anti-HIV agents. Agents able to interfere with additional steps of viral replication, such as integration of viral DNA in the host genome, would improve the antiviral potency of the treatment. In this regard, we have focused our interest on peptide-based compounds that have been shown to exhibit potential inhibition of RT and integrase (IN) activities in vitro and in vivo. Recently, the expansion of powerful technologies which allow the selection of peptides exhibiting high affinity for a target protein have provided a new approach to selecting potential anti-HIV drugs. Furthermore, efforts to characterize the protein-protein interactions involved in efficient reverse transcription and integration, as well as the determination of the enzyme structure, have generated a very useful source of data for the development of peptide inhibitors. Finally, while this class of compounds has long been considered as poor drug candidates, current knowledge on improving the stability and bioavailability of these agents would lead to the effective use of peptides in therapy.
目前，人类免疫缺陷病毒1型（HIV-1）感染的治疗方法是将靶向逆转录酶（RT）和蛋白酶（PR）的药物联合使用。尽管这种联合疗法具有多种临床益处，但耐药性的出现凸显了对新型抗HIV药物的需求。能够干扰病毒复制其他步骤的药物，如病毒DNA整合到宿主基因组中，将提高治疗的抗病毒效力。在这方面，我们将兴趣集中在基于肽的化合物上，这些化合物已被证明在体外和体内对RT和整合酶（IN）活性具有潜在抑制作用。最近，强大技术的扩展使得能够选择对靶蛋白具有高亲和力的肽，这为筛选潜在的抗HIV药物提供了一种新方法。此外，对高效逆转录和整合过程中涉及的蛋白质-蛋白质相互作用进行表征以及确定酶结构的努力，为肽抑制剂的开发产生了非常有用的数据源。最后，虽然这类化合物长期以来被认为是较差的药物候选物，但目前关于提高这些药物稳定性和生物利用度的知识将使肽在治疗中得到有效应用。
