Structure-based characterization of novel TRPV5 inhibitors

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Taylor Et Hughes1, John Smith Del Rosario2, Abhijeet Kapoor3

  • 1Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.

Elife
|October 25, 2019
PubMed

Insights

Researchers identified novel inhibitors for the calcium channel TRPV5, crucial for kidney function. These compounds offer new ways to study and treat conditions like hypercalcemia and kidney stones.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Transient receptor potential vanilloid 5 (TRPV5) is a key regulator of calcium reabsorption in the kidney.
  • Limited availability of specific TRPV5 modulators hinders research into calcium-related diseases like hypercalcemia and nephrolithiasis.

Purpose of the Study:

  • To identify novel, potent, and specific modulators of the TRPV5 channel.
  • To elucidate the structural basis for selective TRPV5 inhibition and guide future drug design.

Main Methods:

  • Structure-based virtual screening (SBVS) of potential TRPV5 inhibitors.
  • Electrophysiology screening to assess channel activity.
  • Cryo-electron microscopy (Cryo-EM) to determine inhibitor-bound structures.

Main Results:

  • Three novel TRPV5 inhibitors were identified.
  • One inhibitor demonstrated high affinity and selectivity for TRPV5 over other TRP channels, including TRPV6.
  • Cryo-EM revealed new binding sites for the inhibitors on TRPV5.

Conclusions:

  • Novel inhibitors provide valuable tools for studying TRPV5 function in physiological and pathological contexts.
  • The identified binding sites and mechanism of action pave the way for rational design of next-generation TRPV5 modulators.
  • This work advances the potential therapeutic strategies for calcium homeostasis disorders.
Keywords:
Cryo-EMS. cerevisiaeTRP channelTRPV5inhibitorsion channalmolecular biophysicsstructural biologystructure-based virtual screening

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