摘要详情
4 / 2021-06-28 13:03:47
De novo design of peptidic positive allosteric modulators targeting TRPV1 with analgesic effects
TRPV1,protein design,pain
摘要待审
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, we de novo designed peptidic positive allosteric modulators (PAMs) based on the high-resolution structure of the TRPV1 intracellular ankyrin-repeat like domain. We optimized the hot-spot centric approach (OHCA) for protein design; its usage in Rosetta increased the success rate in protein binder design. We demonstrated experimentally, with a combination of 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 we designed. We 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.
重要日期
-
会议日期
08月06日
2021
至08月09日
2021
-
08月09日 2021
注册截止日期
主办单位
中国神经科学学会离子通道与受体分会
承办单位
河北工业大学
联系方式
- Prof. An
- ha******@hebut.edu.cn
历届会议
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2017年06月23日 中国 Qingdao,China
第六届国际离子通道学术大会 -
2015年06月26日 中国 泸州市
第五届国际离子通道大会 -
2013年06月30日 中国 石家庄市
第4届国际离子通道会议
