AR Sawkar

B Rigat

Bruno Hay Mele

C Porto

CL Newton

DC Devor

E Goldin

G Andreotti

G Parenti

GH Maegawa

Giuseppina Andreotti

GM Martin

GW Carlile

I Bendikov-Bar

J Lukas

K Ishihara

M Tierney

Maria Vittoria Cubellis

R Maitra

T Okumiya

V Law

Valentina Citro

Orphanet Journal of Rare Diseases

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Hay Mele et al. Orphanet Journal of Rare Diseases  (2015) 10:55 DOI 10.1186/s13023-015-0273-2LETTER TO THE EDITOR Open AccessDrug repositioning can accelerate discovery ofpharmacological chaperonesBruno Hay Mele1, Valentina Citro2, Giuseppina Andreotti3* and Maria Vittoria Cubellis2*AbstractA promising strategy for the treatment of genetic diseases, pharmacological chaperone therapy, has been proposedrecently. It exploits small molecules which can be administered orally, reach difficult tissues such as the brain andhave low cost. This strategy has a vast field of application. In order to make drug development as fast as possible, itis important to exploit drug repositioning. We evaluated the impact and limitations of this approach for rarediseases and we provide a shortcut in finding drugs for off-target usage.Keyword: Pharmacological chaperone, Drug repositioningCorrespondence/FindingsA large share of mutations associated to human diseasescauses the destabilization of specific proteins. The activ-ity of unstable proteins can be rescued by small mole-cules that act as pharmacological chaperones (PC).Usually PC are inhibitors or antagonists of their targetsused at a very low concentration, but other types of mol-ecules such as activators or allosteric ligands, which donot reduce activity, would be more appropriate [1-3].There is a limit in this approach because not all the ge-notypes of a given disease are eligible for therapy withPC and only in some cases is it possible to predict theresponsiveness of specific mutations [4].Drug repositioning could accelerate the discovery of PC.The first successful case is provided by imino-sugars thatinterfere with N-glycosylation in cells infected by envel-oped viruses, deoxynojirimcin and its derivatives [5].Clinical trials for the treatment of HIV with deoxynojirim-cines were unsuccessful, because the antiviral concentra-tion required could not be achieved in humans. Howeverthe same imino-sugars could be used as PC at low concen-tration for a different target, glucosylceramidase (Uniprot:P04062), to treat Gaucher disease (MIM: 230800) [6] andlysosomal alpha-glucosidase (Uniprot: P10253), to treatPompe disease (MIM: 232300) [7,8]. The usage of imino-* Correspondence: giuseppina.andreotti@icb.cnr.it; cubellis@unina.it3Istituto di Chimica Biomolecolare –CNR, Pozzuoli, Italy2Department of Biology, University Federico II, Naples, ItalyFull list of author information is available at the end of the article© 2015 Hay Mele et al.; licensee BioMed CentCommons Attribution License (http://creativecreproduction in any medium, provided the orDedication waiver (http://creativecommons.orunless otherwise stated.sugars was then extended to other lysosomal glycosidasesto cure some storage disorders.Drug repositioning should be run systematically forthe discovery of PC. To support our proposal we gath-ered all the proteins that are associated to rare diseases,i.e. the entries that have a link to Orphanet [9] in Uni-prot (Orphan_proteins). For 608 entries out of a total of3289 Orphan_proteins we found a link to DrugBank, adatabase including FDA-approved small molecules, ex-perimental and nutraceuticals drugs [10]. DrugBank an-notates each record with the known pharmacologicalprotein target, but also with other proteins that are acti-vated or inhibited by the drug. In the vast majority ofcases, links between Orphan_proteins and drugs onlyindicate relations documented in the literature, but donot implicate a recognized pharmacological action of thedrug on the target. The histogram in Figure 1 showsthat several Orphan_proteins interact with one or moreapproved small molecules and the list is provided inAdditional file 1. Since our aim is to support theusefulness of repositioning, we excluded biotech drugsbecause some of them have already been approved forenzyme replacement therapy of rare diseases. We alsoexcluded cytochromes, which contribute to the metabol-ism of many drugs. Small chemicals that interact withOrphan_proteins are excellent starting points to developPC. A proof of concept is represented by a paper whichral. This is an Open Access article distributed under the terms of the Creativeommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andiginal work is properly credited. The Creative Commons Public Domaing/publicdomain/zero/1.0/) applies to the data made available in this article,Figure 1 Orphan_Protein distribution per drug. Proteins associatedto rare diseases are ordered by a number of interacting small moleculeFDA-approved drugs.Hay Mele et al. Orphanet Journal of Rare Diseases  (2015) 10:55 Page 2 of 3appeared in 2015 [11] where a screening of 3200 knowndrugs from commercial compound libraries led to theidentification of Ibuprofen as a corrector of the transmem-brane conductance regulator (CFTR) (Uniprot: P13569).Ibuprofen has a pharmacological action on Prostaglandinsynthase 1 and 2 (Uniprot: P35354, P23219), but besidesthis action, DrugBank reports the inhibition of CFTRbased on a paper published in 1998 [12].In addition, we found several other cases in whichsmall approved drugs were successfully repositioned asPC for rare diseases: doxorubicin, an anti-neoplasticanthracycline, for Cystic fibrosis (MIM: 219700) [13],Diltiazem, an antihypertensive, for Gaucher disease(MIM: 230800) [14], Ambroxol, a mucolytic agent, forGaucher and for Fabry disease (MIM: 301500) [15,16],Acetylcysteine, another mucolytic agent, for Pompe dis-ease (MIM: 232300) [17], Pyrimethamine, an anti-parasiticcompound, for GM2 gangliosidosis (MIM: 272800) [18],carbamazepine, a dibenzazepine, for HyperinsulinemicHypoglycemia (MIM: 256450) [19] and Salicylate for Pen-dred Syndrome (MIM: 274600) [20].In these cases, however, the link between the drug andthe Orphan_protein, could not be found in DrugBank.This absence of annotation shows how difficult it is tomine the literature and we admit that also our list ofapproved drugs tested as PC may be incomplete. Thedevelopment of drugs for rare diseases would benefitfrom a mechanism that favours the deposition of dataconcerning the interaction of small molecules and pro-teins into databanks.Additional fileAdditional file 1: Orphan_Proteins associated to approved smallmolecules are listed. The column headings are: Entry, Uniprot ID; EntryName, Uniprot entry name; Status, reviewed if SWISS-Prot entry; Proteinnames, protein full name; Gene names, Names of each gene associated to theprotein; DrugBank cross-reference, List of drugs associated (by DrugBankID);Orphanet cross-reference: List of orphan diseases (by OrphanID) associated tothe protein.AbbreviationsPC: Pharmacological chaperone; CFTR: Cystic fibrosis transmembraneconductance regulator.Competing interestsMVC was a consultant for Shire HGT.Authors’ contributionsGA and MVC designed the study and wrote the paper. BHM and VC carriedout data-mining. All authors read and approved the final manuscript.AcknowledgementsThe financial support of Telethon - Italy (Grant no. GGP12108) and PONRicerca e Competitività 2007–2013 (02_00619_3461281) are gratefullyacknowledged.Author details1Department of Agricultural and Food Sciences, University Federico II, Naples,Italy. 2Department of Biology, University Federico II, Naples, Italy. 3Istituto diChimica Biomolecolare –CNR, Pozzuoli, Italy.Received: 30 March 2015 Accepted: 23 April 2015References1. Goldin E, Zheng W, Motabar O, Southall N, Choi JH, Marugan J, et al. Highthroughput screening for small molecule therapy for Gaucher disease usingpatient tissue as the source of mutant glucocerebrosidase. PLoS One.2012;7(1):e29861.2. Newton CL, Whay AM, McArdle CA, Zhang M, van Koppen CJ, van deLagemaat R, et al. Rescue of expression and signaling of human luteinizinghormone G protein-coupled receptor mutants with an allosterically bindingsmall-molecule agonist. Proc Natl Acad Sci U S A. 2011;108(17):7172–6.3. Andreotti G, Cabeza De Vaca I, Poziello A, Monti MC, Guallar V, Cubellis MV.Conformational response to ligand binding in Phosphomannomutase2:insights into inborn glycosylation disorder. J Biol Chem. 2014;289(50):34900–10.4. Andreotti G, Guarracino MR, Cammisa M, Correra A, Cubellis MV. Predictionof the responsiveness to pharmacological chaperones: lysosomal humanalpha-galactosidase, a case of study. Orphanet J Rare Dis. 2010;5:36.5. Tierney M, Pottage J, Kessler H, Fischl M, Richman D, Merigan T, et al. Thetolerability and pharmacokinetics of N-butyl-deoxynojirimycin in patientswith advanced HIV disease (ACTG 100). The AIDS Clinical Trials Group(ACTG) of the National Institute of Allergy and Infectious Diseases. J AcquirImmune Defic Syndr Hum Retrovirol. 1995;10(5):549–53.6. Sawkar AR, Cheng WC, Beutler E, Wong CH, Balch WE, Kelly JW. Chemicalchaperones increase the cellular activity of N370S beta -glucosidase: atherapeutic strategy for Gaucher disease. Proc Natl Acad Sci U S A.2002;99(24):15428–33.7. Okumiya T, Kroos MA, Vliet LV, Takeuchi H, Van der Ploeg AT, Reuser AJ.Chemical chaperones improve transport and enhance stability of mutantalpha-glucosidases in glycogen storage disease type II. Mol Genet Metab.2007;90(1):49–57.8. Parenti G, Zuppaldi A, Gabriela Pittis M, Rosaria Tuzzi M, Annunziata I,Meroni G, et al. Pharmacological enhancement of mutated alpha-glucosidase activity in fibroblasts from patients with Pompe disease. MolTher. 2007;15(3):508–14.9. Orphanet. Orphanet. 2015. http://www.orpha.net/consor/cgi-bin/index.php.10. Law V, Knox C, Djoumbou Y, Jewison T, Guo AC, Liu Y, et al. DrugBank 4.0:shedding new light on drug metabolism. Nucleic Acids Res.2014;42(Database issue):D1091–7.Hay Mele et al. Orphanet Journal of Rare Diseases  (2015) 10:55 Page 3 of 311. 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Hear Res. 2010;270(1–2):110–8.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color ﬁgure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submit

Drug repositioning can accelerate discovery of pharmacological chaperones

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Drug repositioning can accelerate discovery of pharmacological chaperones

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