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Chemical Science View Article Online PERSPECTIVE View Journal | View Issue Tuning protein folding in lysosomal storage diseases: the chemistry behind pharmacological Cite this: Chem. Sci.,2018,9,1740 chaperones David M. Pereira, * Patr´ıcia Valentao˜ and Paula B. Andrade Received 31st October 2017 Misfolding of proteins is the basis of several proteinopathies. Chemical and pharmacological chaperones Accepted 10th January 2018 are small molecules capable of inducing the correct conformation of proteins, thus being of interest for DOI: 10.1039/c7sc04712f human therapeutics. The most recent developments in medicinal chemistry and in the drug rsc.li/chemical-science development of pharmacological chaperones are discussed, with focus on lysosomal storage diseases. 1 Introduction a wide range of deleterious effects and has been associated with the pathophysiology of several diseases, notably Alzheimer's Proteins are essential for life, with protein function being disease (AD), Parkinson's disease (PD) and Huntington's.1,2 In Creative Commons Attribution-NonCommercial 3.0 Unported Licence. largely affected by their tridimensional structure. Folding of other cases, the misfolding of proteins results in a lack of proteins may take place in several cellular locations, including catalytic activity towards their corresponding substrates. To the cytoplasm mitochondria, nucleus and also the endo- cope with these misfolding events, cells have developed plasmic reticulum (ER), the latter retaining polypeptides in the a protein quality control (PQC) system that oversees protein event that they are unable to correctly fold and being unable to folding and is ultimately aimed to induce or restore proper be further trafficked to the Golgi apparatus and other protein folding.3 This complex system relies on the unfolded organelles. protein response (UPR) in the ER, which attenuates protein When a misfolding event takes place, which may be synthesis and, in advanced stages, the proteolytic activity of the This article is licensed under a a consequence of either environmental factors or mutations 26S proteasome via endoplasmic reticulum-associated protein that impact protein conformation, proteins may expose hydro- degradation (ERAD, Fig. 2).4 phobic segments that would not normally be available, which Chaperones are molecules capable of assisting proteins into may result in intermolecular binding with other proteins and their correct conformation. Considering that in several protei- Open Access Article. Published on 10 January 2018. Downloaded 9/30/2021 12:35:05 PM. subsequent aggregation (Fig. 1, le). This aggregation has nopathies, the restoration of just 10–20% of protein activity is enough to prevent clinical manifestations of the disease,5–7 REQUIMTE/LAQV, Laboratorio´ de Farmacognosia, Departamento de Qu´ımica, chaperone-based therapy emerges as promising targets for Faculdade de Farmacia,´ Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, countering diseases that result from protein misfolding. 4050-313 Porto, Portugal. E-mail: dpereira@ff.up.pt David M. Pereira obtained his Patr´ıcia Valentao˜ obtained her PhD in Pharmaceutical Sciences PhD in Pharmaceutical Sciences at the University of Porto for his at the University of Porto for her work on Phytochemistry and work on pharmacognosy. She Pharmacognosy. In 2014, he was was appointed Assistant appointed Assistant Professor at Professor at the same university the Faculty of Pharmacy at the in 2010. Her research focuses on same university. His research qualitative and quantitative interests focus on natural prod- metabolite proling of terres- ucts chemistry and biological trial and marine natural assessment of small molecules. matrices with the goal to reveal In particular, he is interested in the composition/activity rela- small molecular modulators of tionships of these compounds in endoplasmic reticulum stress and the proteostasis network, with various clinically relevant areas. connections to cancer and inammation. 1740 | Chem. Sci.,2018,9,1740–1752 This journal is © The Royal Society of Chemistry 2018 View Article Online Perspective Chemical Science Fig. 1 Impact of protein misfolding on protein aggregation (left) and rescue by hydrophobic chaperones (right). Chaperones can be sorted in three groups according to their hydrophilic protein backbone minimizes its exposure to the chemical structure and mechanism of action: molecular, hydrophobic surroundings.10 In this light, the osmolyte mech- chemical and pharmacological. Molecular chaperones that are anism of action is generally universal, being mostly indepen- themselves proteins will not be discussed here. dent of the primary sequence and affecting all proteins. From a chemical point of view, several classes of compounds may act as osmolytes, including free amino acids and their derivatives 2 The chemistry of chaperones (taurine, b-alanin, glycine, etc.), polyols (glycerol, trehalose, Creative Commons Attribution-NonCommercial 3.0 Unported Licence. sucrose, etc.) or methylamines (trimethylamine N-oxide 2.1 Chemical chaperones [TMAO]). Chemical chaperones are low molecular weight molecules that Physiologically, the contribution of each osmolyte to the display a nonspeci c mode of action and are frequently unable overall stability of proteins seems to be dependent on the to bind directly to proteins. From a functional point of view, specic stress environment. For instance, polyols protect cells these molecules can be sorted either as osmolytes or hydro- against dehydration and extreme temperatures, amino acids 3 phobic compounds. are useful in situations involving high salinity and methyl- 2.1.1 Osmolytes. Cellular osmolytes are evolutionary- amines are found predominantly in urea-rich cells because of selected uncharged or zwitter molecules that contribute to urea's deleterious effects on protein structure.9 This article is licensed under a cellular coping under a myriad of stress conditions including 2.1.2 Hydrophobic chaperones. Unfolded proteins usually 8,9 salinity changes, desiccation or extreme temperatures. display hydrophobic regions, which renders them prone to Osmolytes can alter solvent properties, thus forcing ther- establish intermolecular bonds with other unfolded proteins, modynamically unstable proteins to fold and stabilize.10 The Open Access Article. Published on 10 January 2018. Downloaded 9/30/2021 12:35:05 PM. thus resulting in aggregation (Fig. 1, le). By interacting with ff physical chemistry behind the ability of osmolytes to a ect the exposed hydrophobic segments of unfolded proteins, protein stability is elegantly simple: due to their ability to hydrophobic chaperones act as protectors, ultimately prevent- sequester water molecules, osmolytes create a hydrophobic ing protein aggregation (Fig. 1, right). environment around proteins, hence increasing the free energy 4-Phenylbutyrate (4-PBA, 1) is one of the most well-known of the unfolded state and favoring the folded state because the chemical chaperones. This short-chain fatty acid is orally bioavailable and blood–brain barrier (BBB) permeable, the latter property being particularly interesting Paula B. Andrade is an Associate inlightofitssignicant neuroprotective effect in animal Professor at the Faculty of Phar- models of neurodegenerative diseases, such as AD11,12 macy of the University of Porto. and PD.13,14 Several derivatives have already been obtained She coordinates the Natural (2–4), and their structure–activity relationship (SAR) Products group of the investigated.4 REQUIMENTE/LAQV, an insti- tute active in Green Chemistry, and evaluates research projects for various international entities. Her research on bioactive substances originating from matrices of marine and terres- trial origin was published in more than 30 book chapters and over 300 articles in international journals. This journal is © The Royal Society of Chemistry 2018 Chem. Sci.,2018,9,1740–1752 | 1741 View Article Online Chemical Science Perspective Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Fig. 2 Overall view of the folding and quality control check of proteins in the ER, followed by subsequent trafficking to the Golgi apparatus. In the case of lysosomal storage diseases, pharmacological chaperones (PC) promote the correct folding of proteins in the ER, allowing the protein to reach the lysosome where, because of acidic pH and high substrate concentration, PC dissociates from the enzyme, thus delivering a functional protein. ERAD – endoplasmic reticulum-associated protein degradation. This article is licensed under a 4-PBA was approved by the Food and Drug Administration as 2.2 Pharmacological chaperones an ammonium scavenger for the treatment of urea cycle disor- Pharmacological chaperones (PCs) are molecules of low Open Access Article. Published on 10 January 2018. Downloaded 9/30/2021 12:35:05 PM. ders in children.5 Clinical trials have also shown its potential in molecular weight that bind to proteins and can induce ther- the treatment of sickle cell disease and thalassemia, which is modynamic stabilization, template-based induction of correct associated to its ability to activate b-globin transcription.6 folding or changes in the folding/unfolding kinetics,8 thus Bile acids (BAs) are (acidic) steroids biosynthesized from contributing to correct protein function.9 cholesterol in the liver. Upon secretion in the intestine, they can In a rather contra-intuitive discovery in 1990, it was found be metabolized by bacteria that perform dehydroxylation reac- that