De Novo Design of Peptidic Positive Allosteric Modulators Targeting TRPV1 with Analgesic Effects.
De Novo Design of Peptidic Positive Allosteric Modulators Targeting TRPV1 with Analgesic Effects.
复制标题
具有镇痛作用的靶向 TRPV1 的肽正变构调节剂的从头设计
DOI：
10.1002/advs.202101716
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Yang F
中科院分区：
文献类型：
--
作者：
Xu L;Zhang H;Wang Y;Lu X;Zhao Z;Ma C;Yang S;Yarov-Yarovoy V;Tian Y;Zheng J;Yang F
瞬时受体电位香草酸1（TRPV 1）离子通道是一种与痛觉密切相关的伤害感受器。TRPV 1的直接阻断表现出显著的镇痛作用，但也引起严重的副作用，如高热，导致TRPV 1抑制剂在临床试验中失败。为了选择性靶向积极参与疼痛感受的TRPV 1通道，重新设计了基于TRPV 1细胞内锚蛋白重复样结构域的高分辨率结构的肽正变构调节剂（PAM）。以热点为中心的方法针对蛋白质设计进行了优化;它在Rosetta中的使用提高了蛋白质结合剂设计的成功率。通过荧光共振能量转移（FRET）成像、表面等离子体共振和膜片钳记录的组合，实验证明，所设计的PAM以纳摩尔亲和力结合TRPV 1，并在设计时变构增强其对配体活化的反应。进一步证明了所设计的PAM在大鼠中表现出持久的体内镇痛作用而不改变其体温，表明它们具有开发成新型镇痛剂的潜力。瞬时受体电位香草酸1（TRPV 1）离子通道在痛觉中起重要作用。TRPV 1的正变构调节剂（PAM）是基于TRPV 1的结构重新设计的。表面等离子体共振和膜片钳记录表明PAM与TRPV 1结合并变构增强其活性。PAM对大鼠有镇痛作用，但不改变体温。
Transient receptor potential vanilloid 1 (TRPV1) ion channel is a nociceptor critically involved in pain sensation. Direct blockade of TRPV1 exhibits significant analgesic effects but also incurs severe side effects such as hyperthermia, causing failures of TRPV1 inhibitors in clinical trials. In order to selectively target TRPV1 channels that are actively involved in pain‐sensing, peptidic positive allosteric modulators (PAMs) based on the high‐resolution structure of the TRPV1 intracellular ankyrin‐repeat like domain are de novo designed. The hotspot centric approach is optimized for protein design; its usage in Rosetta increases the success rate in protein binder design. It is demonstrated experimentally, with a combination of fluorescence resonance energy transfer (FRET) imaging, surface plasmon resonance, and patch‐clamp recording, that the designed PAMs bind to TRPV1 with nanomolar affinity and allosterically enhance its response to ligand activation as it is designed. It is further demonstrated that the designed PAM exhibits long‐lasting in vivo analgesic effects in rats without changing their body temperature, suggesting that they have potentials for developing into novel analgesics. Transient receptor potential vanilloid 1 (TRPV1) ion channel is critically involved in pain sensation. Positive allosteric modulators (PAMs) of TRPV1 are de novo designed based on the structure of TRPV1. Surface plasmon resonance and patch‐clamp recording demonstrate that the PAMs bind to TRPV1 and allosterically enhance its activities. The PAM exhibits analgesic effects without changing body temperature in rats.
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DOI：
10.1085/jgp.201210810
发表时间：
2012-11
期刊：
The Journal of general physiology
影响因子：
--
作者：
Lau SY;Procko E;Gaudet R
通讯作者：
Gaudet R
影响因子：
14.9
作者：
Schneidman-Duhovny D;Inbar Y;Nussinov R;Wolfson HJ
通讯作者：
Wolfson HJ
影响因子：
5.6
作者：
Fleishman, Sarel J.;Corn, Jacob E.;Strauch, Eva-Maria;Whitehead, Timothy A.;Karanicolas, John;Baker, David
通讯作者：
Baker, David
DOI：
10.1016/b978-0-12-396493-9.00002-9
发表时间：
2012-01-01
期刊：
PROGRESS IN MEDICINAL CHEMISTRY, VOL 51
影响因子：
--
作者：
Kort, Michael E.;Kym, Philip R.
通讯作者：
Kym, Philip R.
影响因子：
16.2
作者：
Erickson, MG;Alseikhan, BA;Yue, DT
通讯作者：
Yue, DT