Introducing metallocene into a triazole peptide conjugate reduces its off-rate and enhances its affinity and antiviral potency for HIV-1 gp120.
Introducing metallocene into a triazole peptide conjugate reduces its off-rate and enhances its affinity and antiviral potency for HIV-1 gp120.
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DOI：
10.1002/jmr.892
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发表时间：
2009-03
影响因子：
2.7
通讯作者：
Chaiken, Irwin M.
中科院分区：
文献类型：
--
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.
在这项工作中，我们确定了一种高亲和力和效力的含三唑的三唑肽缀合物，其抑制HIV-1包膜gp 120在其CD 4和辅助受体结合位点的相互作用。二茂铁-肽缀合物HNG-156通过树脂上铜催化的[2 + 3]环加成反应形成。表面等离子体共振相互作用分析显示，与先前报道的含苯基的三唑缀合物HNG-105（105）相比，肽156对HIV-1 gp 120的几种亚型具有更高的直接结合亲和力，这主要是由于缀合物-gp 120复合物的解离速率降低。二茂铁三唑缀合物以纳摩尔KD直接结合进化枝A（92 UG 037 -08）和进化枝B（YU-2和SF 162）病毒亚型的gp 120，并抑制gp 120与可溶性CD 4和在CD 4结合位点和CD 4诱导的结合位点与HIV-1 YU-2 gp 120结合的抗体的结合。HNG-156对HIV-1BaL全病毒的细胞感染的抑制IC 50接近纳摩尔。HNG-156的双重受体位点拮抗剂活性和效力使其成为开发抗HIV-1治疗的有前景的病毒包膜抑制剂。
In this work, we identified a high affinity and potency metallocene-containing triazole peptide conjugate that suppresses the interactions of HIV-1 envelope gp120 at both its CD4 and co-receptor binding sites. The ferrocene-peptide conjugate, HNG-156, was formed by an on-resin copper-catalysed [2 + 3] cycloaddition reaction. Surface plasmon resonance interaction analysis revealed that, compared to a previously reported phenyl-containing triazole conjugate HNG-105 (105), peptide 156 had a higher direct binding affinity for several subtypes of HIV-1 gp120 due mainly to the decreased dissociation rate of the conjugate-gp120 complex. The ferrocene triazole conjugate bound to gp120 of both clade A (92UG037-08) and clade B (YU-2 and SF162) virus subtypes with nanomolar KD in direct binding and inhibited the binding of gp120 to soluble CD4 and to antibodies that bind to HIV-1YU-2 gp120 at both the CD4 binding site and CD4-induced binding sites. HNG-156 showed a close-to nanomolar IC50 for inhibiting cell infection by HIV-1BaL whole virus. The dual receptor site antagonist activity and potency of HNG-156 make it a promising viral envelope inhibitor lead for developing anti-HIV-1 treatments.
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DOI：
10.1073/pnas.1932511100
发表时间：
2003-09-16
影响因子：
11.1
作者：
Moore, JP;Doms, RW
通讯作者：
Doms, RW
影响因子：
7.6
作者：
Krebs, FC;Miller, SR;Wigdahl, B
通讯作者：
Wigdahl, B
DOI：
10.1073/pnas.96.23.13091
发表时间：
1999-11-09
影响因子：
11.1
作者：
Vita, C;Drakopoulou, E;Gluckman, JC
通讯作者：
Gluckman, JC
影响因子：
3.4
作者：
Gopi, Hosahudya N.;Tirupula, Kalyan C.;Chaiken, Irwin M.
通讯作者：
Chaiken, Irwin M.
影响因子：
32.4
作者：
Cardoso, RMF;Zwick, MB;Wilson, IA
通讯作者：
Wilson, IA