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Cell-Based Small-Molecule Screening Identifying Proteostasis Regulators Enhancing Factor VIII Missense Mutant

Vishal Srivastava1, Zhigang Liu1, Wei Wei1

  • 1Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.

Biomolecules
|April 30, 2025
PubMed
Summary
This summary is machine-generated.

Suberoylanilide hydroxamic acid (SAHA) enhances the secretion and activity of coagulation factor VIII (FVIII) in hemophilia A models. This proteostasis regulator offers a promising therapeutic strategy for FVIII missense mutations.

Keywords:
BiP/GRP78Vorinostatfactor VIIIproteostasis regulatorssecretion

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Area of Science:

  • Biochemistry
  • Genetics
  • Pharmacology

Background:

  • Missense mutations are primary causes of hemophilia A (HA), leading to coagulation factor VIII (FVIII) deficiencies.
  • Current HA treatments are costly and inconvenient, necessitating accessible alternatives.
  • Small molecule drugs present a viable option for improving HA management.

Purpose of the Study:

  • To identify compounds that enhance FVIII secretion and activity.
  • To evaluate suberoylanilide hydroxamic acid (SAHA) as a potential therapeutic agent for HA.
  • To elucidate the mechanism of SAHA's action on FVIII secretion.

Main Methods:

  • Screening drug libraries using cells expressing FVIII-Gaussia luciferase fusion proteins.
  • Assessing SAHA's effect on wild-type and mutant FVIII secretion and activity in vitro.
  • Investigating SAHA's interaction with endoplasmic reticulum chaperones (BiP/GRP78, calreticulin).
  • Evaluating SAHA's efficacy in a mouse model of HA.

Main Results:

  • SAHA significantly improved secretion and activity of wild-type FVIII and common HA missense mutants.
  • SAHA enhanced FVIII interaction with BiP/GRP78, a key chaperone in protein folding.
  • Modulating BiP levels affected SAHA-induced FVIII secretion, confirming BiP's role.
  • In vivo administration of SAHA or a BiP activator increased endogenous FVIII activity in mice.

Conclusions:

  • SAHA acts as a proteostasis regulator, enhancing FVIII secretion and function.
  • SAHA represents a novel therapeutic strategy for HA caused by FVIII missense mutations.
  • Targeting chaperone interactions offers a promising approach for treating genetic disorders involving protein misfolding.