Virtual Evolution of HVEM Segment for Checkpoint Inhibitor Discovery.
Virtual Evolution of HVEM Segment for Checkpoint Inhibitor Discovery.
复制标题
用于检查点抑制剂发现的 HVEM 部分的虚拟演化
DOI：
10.3390/ijms22126638
复制
发表时间：
2021-06-21
影响因子：
5.6
通讯作者：
Xue S
中科院分区：
文献类型：
--
作者：
Yu M;Zhao H;Miao Y;Luo SZ;Xue S
免疫疗法已成为一种有效的癌症治疗方法。受PD-1/PD-L1抗体在临床上取得巨大成功的启发，其他免疫检查点蛋白在癌症研究中引起了越来越多的关注。B和T淋巴细胞衰减因子（BTLA）和疱疹病毒进入介体（HVEM）是药物开发的潜在靶点。BTLA/HVEM共晶结构分析表明，HVEM（26-38）片段是BTLA/HVEM共晶结构的核心序列，直接作用于BTLA/HVEM的界面。在此，我们进行虚拟进化与此序列，通过使用饱和诱变在硅片和突变体具有较低的结合能进行选择。湿实验室实验证实，其中几个具有较高的亲和力与BTLA。在核心序列最佳突变体的基础上，获得了药效更好的延伸肽。此外，突变的影响机制，揭示了通过计算分析。本文发现的突变肽可能是阻断BTLA/HVEM相互作用的有效抑制剂，其机制可能扩展人们对检查点对抑制剂发现的看法。
Immune therapy has emerged as an effective treatment against cancers. Inspired by the PD-1/PD-L1 antibodies, which have achieved great success in clinical, other immune checkpoint proteins have drawn increasing attention in cancer research. B and T lymphocyte attenuator (BTLA) and herpes virus entry mediator (HVEM) are potential targets for drug development. The co-crystal structure of BTLA/HVEM have revealed that HVEM (26–38) fragment is the core sequence which directly involved on the interface. Herein, we conducted virtual evolution with this sequence by using saturation mutagenesis in silico and mutants with lower binding energy were selected. Wet-lab experiments confirmed that several of them possessed higher affinity with BTLA. Based on the best mutant of the core sequence, extended peptides with better efficacy were obtained. Furthermore, the mechanism of the effects of mutations was revealed by computational analysis. The mutated peptide discovered here can be a potent inhibitor to block BTLA/HVEM interaction and its mechanism may extend people’s view on inhibitor discovery for the checkpoint pair.
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DOI：
10.1016/j.str.2020.07.013
发表时间：
2020-11-03
期刊：
Structure (London, England : 1993)
影响因子：
--
作者：
Shrestha R;Garrett-Thomson SC;Liu W;Almo SC;Fiser A
通讯作者：
Fiser A
影响因子：
5.6
作者：
de Jong FC;Rutten VC;Zuiverloon TCM;Theodorescu D
通讯作者：
Theodorescu D
DOI：
10.1073/pnas.0902115106
发表时间：
2009-04-14
影响因子：
11.1
作者：
Cheung, Timothy C.;Steinberg, Marcos W.;Ware, Carl F.
通讯作者：
Ware, Carl F.
影响因子：
16
作者：
Carfí, A;Willis, SH;Wiley, DC
通讯作者：
Wiley, DC
影响因子：
7.2
作者：
Gertner-Dardenne J;Fauriat C;Olive D
通讯作者：
Olive D