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Polymorphic Structure Determination of the Macrocyclic Drug Paritaprevir by MicroED

G Bu1, E Danelius1,2, L H Wieske3

  • 1Department of Biological Chemistry, University of California Los Angeles, 615 Charles E.Young Drive South, Los Angeles, CA 90095, USA.

Biorxiv : the Preprint Server for Biology
|October 2, 2023
PubMed

Insights

Researchers used MicroED to reveal two crystal forms of paritaprevir, a Hepatitis C drug. This provides insights into drug-protease interactions and inhibitor design for Hepatitis C virus (HCV).

Area of Science:

  • Structural biology
  • Drug discovery
  • Crystallography

Background:

  • Paritaprevir is a macrocyclic drug for Hepatitis C virus (HCV) infection.
  • Its detailed structure was previously unknown, hindering drug optimization.
  • Polymorphism can affect drug bioavailability and efficacy.

Approach:

  • Microcrystal Electron Diffraction (MicroED) was used to determine the structures of two paritaprevir polymorphs.
  • Molecular docking was performed to assess binding interactions with the NS3/4A serine protease.
  • Conformational differences in the macrocyclic core and substituents were analyzed.

Key Points:

  • Two distinct polymorphic crystal forms of paritaprevir were solved from a single experiment using MicroED.
  • Observed conformational variations in the macrocyclic core and substituents.
  • One paritaprevir conformation showed favorable binding to the NS3/4A serine protease active site.

Conclusions:

  • The study demonstrates MicroED's capability to resolve multiple polymorphs and conformations simultaneously.
  • Structural insights aid in optimizing acylsulfonamide inhibitors for HCV NS3/4A serine protease.
  • Findings contribute to a deeper understanding of paritaprevir's structure-activity relationship.
Keywords:
CryoEMHCV ProteaseMacrocyclesMicroEDMolecular ChameleonsPolymorphism

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