Exploiting the Innate Plasticity of the Programmed Cell Death-1 (PD1) Receptor to Design Pembrolizumab H3 Loop Mimics.
Exploiting the Innate Plasticity of the Programmed Cell Death-1 (PD1) Receptor to Design Pembrolizumab H3 Loop Mimics.
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DOI：
10.1002/cbic.202200449
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发表时间：
2022-11-04
期刊：
影响因子：
3.2
通讯作者：
Roche, Stephane P.
中科院分区：
文献类型：
--
作者：
Richaud, Alexis D.;Zaghouani, Mehdi;Zhao, Guangkuan;Wangpaichitr, Medhi;Savaraj, Niramol;Roche, Stephane P.
关键词：
通过单克隆抗体（如pembrolizumab）对免疫受体程序性细胞死亡-1（PD 1）及其配体-1（PDL 1）的检查点阻断在各种癌症类型中提供了令人信服的临床结果，但这种药物阻断PD 1/PDL 1界面的分子机制仍不清楚。为了解决这个问题，我们研究了与pembrolizumab结合相关的PD 1构象运动。我们的研究结果表明，C 'D和FG环的先天可塑性对于在PD 1的几个远距离表位上形成深结合沟（371 μ 3）至关重要。该分析最终提供了在β-发夹支架中产生派姆单抗H3环模拟物[RDYRFDMGFD]的合理设计。因此，20个残基的长β-发夹肽1 e被鉴定为一类有效的PD 1抑制剂（EC 50为0.29 μM; Ki为41 nM）。Bent to Bind. Pembrolizumab是用于免疫肿瘤学的PD 1阻断剂的旗舰产品。PD-1·派姆单抗结合的蓝图显示，通过在PD 1上形成动态凹槽，约40%的总界面位于刚性CDR-H3环外周。这被用来合理地将派姆单抗H3环模拟成更小的β-发夹支架作为PD 1/PDL 1阻断剂。
Checkpoint blockade of the immunoreceptor Programmed Cell Death-1 (PD1) with its ligand-1 (PDL1) by monoclonal antibodies such as pembrolizumab provided compelling clinical results in various cancer types, yet the molecular mechanism by which this drug blocks the PD1/PDL1 interface remains unclear. To address this question, we examined the conformational motion of PD1 associated with the binding of pembrolizumab. Our results revealed that the innate plasticity of both C’D and FG loops is crucial to form a deep binding groove (371 Å3) across several distant epitopes of PD1. This analysis ultimately provided a rational-design to create pembrolizumab H3 loop mimics [RDYRFDMGFD] into β-hairpin scaffolds. As a result, a 20-residue long β-hairpin peptide 1e was identified as a first-in-class potent PD1-inhibitor (EC50 of 0.29 μM; Ki of 41 nM). Bent to Bind. Pembrolizumab is the flagship of PD1 blockers used in immuno-oncology. A blueprint of the PD-1•pembrolizumab binding revealed that ~40% of the total interface resides at the rigid CDR-H3 loop periphery through the formation of a dynamic groove on PD1. This was exploited to rationally mimic the pembrolizumab H3-loop into smaller β-hairpin scaffolds as PD1/PDL1 blockers.
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影响因子：
3.5
作者：
Anderson JM;Kier BL;Shcherbakov AA;Andersen NH
通讯作者：
Andersen NH
影响因子：
4
作者：
Dishman AF;Volkman BF
通讯作者：
Volkman BF
DOI：
10.1073/pnas.0802496105
发表时间：
2008-07-29
影响因子：
11.1
作者：
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通讯作者：
Sternberg, Michael J. E.
影响因子：
7.3
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Guzik, Katarzyna;Zak, Krzysztof M.;Holak, Tad A.
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Holak, Tad A.
影响因子：
4
作者：
Fessas P;Lee H;Ikemizu S;Janowitz T
通讯作者：
Janowitz T