Non-natural peptide triazole antagonists of HIV-1 envelope gp120.
Non-natural peptide triazole antagonists of HIV-1 envelope gp120.
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DOI：
10.1002/cmdc.201200422
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发表时间：
2013-02
期刊：
影响因子：
3.4
通讯作者：
Chaiken, Irwin M.
中科院分区：
文献类型：
--
作者：
Kamanna, Kantharaju;Aneja, Rachna;Duffy, Caitlin;Kubinski, Pamela;Moreira, Diogo Rodrigo;Bailey, Lauren D.;McFadden, Karyn;Schoen, Arne;Holmes, Andrew;Tuzer, Ferit;Contarino, Mark;Freire, Ernesto;Chaiken, Irwin M.
我们对HIV-1Env gp120的非天然多肽三氮唑双受体位点拮抗剂的来源进行了研究，以期为开发拟肽类抗病毒药物开辟一条途径。此前，我们发现三氮唑HNG-156(R-I-N-N-I-X-W-S-E-A-M-M-CONH2，其中X为二茂铁基三氮唑-Pro(Ftp))与gp120具有纳米分子结合亲和力，抑制gp120与cD4和辅受体替代物mAb17b的结合，并在细胞感染实验中具有较强的抗病毒活性。此外，HNG-156的截短变体，以UM-24(Cit-N-N-I-X-W-S-CONH2)为代表，包含关键的中心立体特异性LX-LW簇，保留了母肽三唑的功能特征。在目前的工作中，我们研究了最大限度地用非天然残留物成分取代UM-24中天然残留物的可能性。用L-3-苯并硫基丙氨酸(BTA)(KR-41)取代TrP6为关键“热点”残基的类似物，以及含有中心簇外D-氨基酸取代的完全非天然类似物(KR-42，DCit-dN-dN-DI-X-BTA-ds-CONH2)，保留了双重受体位点拮抗/抗病毒活性特征。这些结果确定了三唑多肽中不同亚域的不同功能，并为设计代谢稳定的HIV-1 env gp120模拟多肽抑制剂提供了结构基础。
We investigated the derivation of non-natural peptide triazole dual receptor site antagonists of HIV-1 Env gp120 in order to establish a path for developing peptidomimetic antiviral agents. Previously, we found that the peptide triazole HNG-156 (R-I-N-N-I-X-W-S-E-A-M-M-CONH2, where X is ferrocenyltriazole-Pro (FtP)) had nanomolar binding affinity to gp120, inhibited gp120 binding to CD4 and the co-receptor surrogate mAb 17b and had potent antiviral activity in cell infection assays. Further, truncated variants of HNG-156, typified by UM-24 (Cit-N-N-I-X-W-S-CONH2) and containing the critical central stereospecific LX-LW cluster, retained the functional characteristics of the parent peptide triazole. In the current work, we examined the possibility to replace natural with unnatural residue components in UM-24 to the greatest extent possible. The analogue with the critical “hot spot” residue Trp 6 replaced with L-3-Benzothienylalanine (Bta) (KR-41), as well as a completely non-natural analogue containing D-amino acid substitutions outside the central cluster (KR-42, DCit-DN-DN-DI-X-Bta-DS-CONH2), retained the dual receptor site antagonism / antiviral activity signature. The results define differential functional roles of subdomains within the peptide triazole and provide a structural basis for designing metabolically stable peptidomimetic inhibitors of HIV-1 Env gp120.
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影响因子：
56.9
作者：
Feng, Y;Broder, CC;Berger, EA
通讯作者：
Berger, EA
影响因子：
64.8
作者：
Liu, Jun;Bartesaghi, Alberto;Borgnia, Mario J.;Sapiro, Guillermo;Subramaniam, Sriram
通讯作者：
Subramaniam, Sriram
影响因子：
64.5
作者：
Eckert, DM;Malashkevich, VN;Kim, PS
通讯作者：
Kim, PS
影响因子：
2.7
作者：
Gopi, Hosahudya;Cocklin, Simon;Pirrone, Vanessa;McFadden, Karyn;Tuzer, Ferit;Zentner, Isaac;Ajith, Sandya;Baxter, Sabine;Jawanda, Navneet;Krebs, Fred C.;Chaiken, Irwin M.
通讯作者：
Chaiken, Irwin M.
影响因子：
120.1
作者：
Flexner, Charles
通讯作者：
Flexner, Charles