Inhibiting HIV-1 entry: Discovery of D-peptide inhibitors that target the gp41 coiled-coil pocket
Inhibiting HIV-1 entry: Discovery of D-peptide inhibitors that target the gp41 coiled-coil pocket
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DOI：
10.1016/s0092-8674(00)80066-5
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发表时间：
1999-10-01
期刊：
影响因子：
64.5
通讯作者：
Kim, PS
中科院分区：
文献类型：
--
作者：
Eckert, DM;Malashkevich, VN;Kim, PS
HIV-1 gp 41蛋白通过介导病毒和细胞膜的融合促进病毒进入。在gp 41内的中央三聚体卷曲螺旋表面上的突出口袋先前被鉴定为抑制HIV-1进入的药物的潜在靶点。我们设计了一种肽IQN 17，它可以正确地呈现这个口袋。利用IQN 17和镜像噬菌体展示，我们确定了共享一个序列基序的HIV-1感染的环状D肽抑制剂。IQN 17与D-肽复合的1.5埃共晶结构和NMR研究表明，这些抑制剂的保守残基与gp 41口袋密切接触。我们的研究验证了口袋本身作为药物开发的目标。IQN 17和这些D-肽抑制剂可能有助于开发和鉴定一类新的口服生物可利用的抗HIV药物。
The HIV-1 gp41 protein promotes viral entry by mediating the fusion of viral and cellular membranes. A prominent pocket on the surface of a central trimeric coiled coil within gp41 was previously identified as a potential target for drugs that inhibit HIV-1 entry. We designed a peptide, IQN17, which properly presents this pocket. Utilizing IQN17 and mirror-image phage display, we identified cyclic, D-peptide inhibitors of HIV-1 infection that share a sequence motif. A1.5 Angstrom cocrystal structure of IQN17 in complex with a D-peptide, and NMR studies, show that conserved residues of these inhibitors make intimate contact with the gp41 pocket. Our studies validate the pocket per se as a target for drug development. IQN17 and these D-peptide inhibitors ave likely to be useful for development and identification of a new class of orally bioavailable anti-HIV drugs.