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

Abstract

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.

Structure-Function Relationships of the Follicle-Stimulating Hormone Receptor

“…The endoplasmic reticulum (ER) is the cell organelle where the life cycle of GPCRs begins; here, the newly synthesized peptide sequence is translocated, folded into secondary and tertiary structures via disulfide bonds formation and assembled into quaternary complexes. Properly folded receptors are then exported to the ER-Golgi intermediate complex and then to the Golgi apparatus and trans-Golgi network; here, processing is completed, and the receptor proteins are ready to complete their outward trafficking to the PM and become exposed to cognate ligands ( 44 , 45 ). Similar to other GPCRs, if the FSHR is not correctly folded the quality control surveillance of the proteosome removes the misfolded receptor.…”

Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations

“…Pharmacological chaperones have ceased to be a niche category and have entered the clinical practice for some rare diseases caused primarily by protein instability. Many reviews exist to cover this subject with different points of view (a few examples [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]). We wanted to contribute by providing the readers with a list of research papers organized per disease that covers the years from 2000 to 2018.…”

Demonstrating aspects of multiscale modeling by studying the permeation pathway of the human ZnT2 zinc transporter

“…In this respect, pharmacoperones are recently emerging as a novel class of hydrophobic small molecules that can bind to mutant misfolded and inactive proteins, thereby restoring their proper folding, subcellular sorting, and function [ 48 , 49 ]; this novel approach is currently known as pharmacoperone drug therapy. These mutant proteins which are associated with various human disorders include enzymes, receptors, channels, and transporters [ 48 , 49 ]. For example, Menkes disease is a neurodegenerative disease presenting with seizures, lethargy and hypotonia, resulting in death in early childhood.…”