De Novo Design of Peptidic Positive Allosteric Modulators Targeting TRPV1 with Analgesic Effects.

ABSTRACT: 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, surfa

SUBMITTER: Xu L 

PROVIDER: S-EPMC8425881 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature