Pharmacoperone drugs: targeting misfolded proteins causing lysosomal storage-, ion channels-, and G protein-coupled receptors-associated conformational disorders

ABSTRACT

Introduction: Conformational diseases are caused by structurally abnormal proteins that cannot fold properly and achieve their native conformation. Misfolded proteins frequently originate from genetic mutations that may lead to loss-of-function diseases involving a variety of structurally diverse proteins including enzymes, ion channels, and membrane receptors. Pharmacoperones are small molecules that cross the cell surface plasma membrane and reach their target proteins within the cell, serving as molecular scaffolds to stabilize the native conformation of misfolded or well-folded but destabilized proteins, to prevent their degradation and promote correct trafficking to their functional site of action. Because of their high specificity toward the target protein, pharmacoperones are currently the focus of intense investigation as therapy for several conformational diseases.

Areas covered: This review summarizes data on the mechanisms leading to protein misfolding and the use of pharmacoperone drugs as an experimental approach to rescue function of distinct misfolded/misrouted proteins associated with a variety of diseases, such as lysosomal storage diseases, channelopathies, and G protein-coupled receptor misfolding diseases.

Expert commentary: The fact that many misfolded proteins may retain function, offers a unique therapeutic opportunity to cure disease by directly correcting misrouting through administering pharmacoperone drugs thereby rescuing function of disease-causing, conformationally abnormal proteins.

KEYWORDS:

• Conformational diseases
• channelopathies
• chemical chaperones
• G protein-coupled receptors
• intracellular trafficking
• misrouting
• lysosomal storage diseases
• pharmacoperones
• pharmacological chaperones
• protein misfolding
• proteostasis
• quality control

Acknowledgments

The authors thank Ari Kleinberg from the RAI-UNAM for the artwork of Figures 1 and 2.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

Research in the authors´ laboratories are supported by grants from CONACyT, Mexico [grant number 240619] and the National University of Mexico (UNAM-CIC) (to A.U.-A), as well as from the American Diabetes Association [grant number 1-12-BS212] and the Fundamental Research Funds for the Central Universities in China [grant number 841712004] (to Y.-X.T.).