Sequence-based design and discovery of peptide inhibitors of HIV-1 integrase: Insight into the binding mode of the enzyme
文献类型：期刊论文
| 作者 | Li, Hui-Yuan; Zawahir, Zahrah; Song, Lai-Dong; Long, Ya-Qiu; Neamati, Nouri |
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2006-07-27 |
| 卷号 | 49期号:15页码:4477-4486 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/jm060307u |
| 文献子类 | Article |
| 英文摘要 | Integration of viral DNA into the host chromosome is an essential step in the HIV life cycle. This process is mediated by integrase (IN), a 32 kDa viral enzyme that has no mammalian counterpart, rendering it an attractive target for antiviral drug design. Herein, we present a novel approach toward elucidating "hot spots" of protein-protein or protein-nucleic acid interactions of IN through the design of peptides that encompass conserved amino acids and residues known to be important for enzymatic activity. We designed small peptides (7 - 17 residues) containing at least one amino acid residue that is important for IN catalytic activities (3'-processing and strand transfer) or viral replication. All these peptides were synthesized on solid phase by fluorenylmethoxycarbonyl (Fmoc) chemistry and evaluated for their inhibition of IN catalytic activities. Such specific sites of interest (i.e., protein-DNA or protein-drug interactions) could potentially be used as drug targets. This novel "sequence walk" strategy across the entire 288 residues of IN has allowed the identification of two peptides NL-6 and NL-9 with 50% inhibitory concentration (IC50) values of 2.7 and 56 AM for strand transfer activity, respectively. Amino acid substitution analysis on these peptides revealed essential residues for activity, and the rational truncation of NL-6 produced a novel hexapeptide (peptide NL6-5) with inhibitory potency equal to that of the parent dodecapeptide (peptide NL-6). More significantly, the retroinverso analogue of NL-6 (peptide RDNL-6) in which the direction of the sequence is reversed and the chirality of each amino acid residue is inverted displayed improved inhibitory potency against 3'-processing of HIV-1 IN by 6-fold relative to the parent NL-6, serving as a metabolically stable derivative for further in vitro and in vivo analyses. |
| WOS关键词 | IMMUNODEFICIENCY-VIRUS TYPE-1 ; REVERSE-TRANSCRIPTASE ; CATALYTIC DOMAIN ; STRAND TRANSFER ; PROTEIN ; IDENTIFICATION ; ORGANIZATION ; SITE |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000239141500006 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/273535]  |
| 专题 | 药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Long, Ya-Qiu |
| 作者单位 | 1.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai Inst Biol Sci,Grad Sch, Shanghai 201203, Peoples R China 2.Univ So Calif, Sch Pharm, Dept Pharmaceut Sci, Los Angeles, CA 90089 USA |
| 推荐引用方式 GB/T 7714 | Li, Hui-Yuan,Zawahir, Zahrah,Song, Lai-Dong,et al. Sequence-based design and discovery of peptide inhibitors of HIV-1 integrase: Insight into the binding mode of the enzyme[J]. JOURNAL OF MEDICINAL CHEMISTRY,2006,49(15):4477-4486. |
| APA | Li, Hui-Yuan,Zawahir, Zahrah,Song, Lai-Dong,Long, Ya-Qiu,&Neamati, Nouri.(2006).Sequence-based design and discovery of peptide inhibitors of HIV-1 integrase: Insight into the binding mode of the enzyme.JOURNAL OF MEDICINAL CHEMISTRY,49(15),4477-4486. |
| MLA | Li, Hui-Yuan,et al."Sequence-based design and discovery of peptide inhibitors of HIV-1 integrase: Insight into the binding mode of the enzyme".JOURNAL OF MEDICINAL CHEMISTRY 49.15(2006):4477-4486. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。