作用于HIV包膜蛋白亚基gp41的多肽类融合抑制剂

HIVgp4 1是病毒包膜上介导HIV与靶细胞膜融合的跨膜糖蛋白 ,其包膜外区包括位于N末端的融合多肽和下游的N末端重复序列 (NHR) ,以及C末端的重复序列(CHR)。衍生于gp4 1NHR和CHR的N 多肽和C 多肽具有抑制HIV与靶细胞融合的活性 ,其中C 多肽T 2 0已获得美国FDA批准 ,成为继逆转录酶抑制剂和蛋白酶抑制剂后的第三类抗艾滋病药物 ,即HIV融合抑制剂。由于T 2 0等为多肽类药物 ,容易被体内蛋白酶降解 ,临床剂量大 ,用基因工程手段难以满足需要 ,因此只能采用多肽合成技术进行生产 ,成本高昂。为此 ,人们希望寻找到具有相似机制的活性短肽 ,或通过多肽设计使活性多肽适合用基因工程进行大规模生产。近年来 ,对N 多肽和C 多肽进行结构改造已成为研究的热点 ,出现了许多相对分子质量较小 ,不容易被内源性蛋白酶降解 ,或者能用基因工程手段生产的活性多肽 ,同时多肽药物抑制HIV感染的作用机制也因此而逐渐清晰起来

Peptidic HIV fusion inhibitors targeting envelope glycoprotein transmembrane subunit gp41

HIV envelope glycoprotein transmembrane subunit gp41 plays a major role in the fusion of viral and target cell membranes. The extracellular region of gp41 consists of N-terminal fusion peptide and downstream N- and C-heptad repeat (NHR and CHR) regions. The peptidesderived from the NHR and CHR regions, designated N- and C-peptides, respectively, have potent inhibitory activity on the HIV mediated cell fusion. C-peptide T-20 has just got the approval of U.S. FDA, which became the first success of one new class anti-HIV agents, named HIV-fusion inhibitors. However, a relatively long peptide such as T-20 suffers from several limitations including proteolytic sensitivity, large dosage, therefore it is unable to produced by gene engineering. Alternately, shorter peptidic fusion inhibitors and active peptides suitable for gene engineering are pursued. In the recent years, this kind of peptide modifications are hot spots in HIV research field and contribute a lot to the inhibitory mechanism of N- and C-peptide.