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      The current state of drug repurposing and rare diseases: an interview with Paul Trippier

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      Author(s): * , 1 ,
      Publication date (Electronic, pub):
      Publication date (Electronic, collection):
      Journal: Future Drug Discovery
      Publisher: Newlands Press Ltd
      Keywords: ALS, drug repurposing, iPSC models, PROTACS, rare diseases

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          Abstract

          Paul Tripper is an Associate Professor of Medicinal Chemistry at the University of Nebraska Medical Center (UNMC, NE, USA) and an Editorial Board member of Future Drug Discovery. Here, he speaks to Managing Editor Francesca Lake about drug repurposing, focusing on the key challenges, its application to rare diseases and what we can look forward to in the future.

          Most cited references12

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          Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation.

          K M Sakamoto, K. -B. Kim, A Kumagai … (2001)
          The intracellular levels of many proteins are regulated by ubiquitin-dependent proteolysis. One of the best-characterized enzymes that catalyzes the attachment of ubiquitin to proteins is a ubiquitin ligase complex, Skp1-Cullin-F box complex containing Hrt1 (SCF). We sought to artificially target a protein to the SCF complex for ubiquitination and degradation. To this end, we tested methionine aminopeptidase-2 (MetAP-2), which covalently binds the angiogenesis inhibitor ovalicin. A chimeric compound, protein-targeting chimeric molecule 1 (Protac-1), was synthesized to recruit MetAP-2 to SCF. One domain of Protac-1 contains the I kappa B alpha phosphopeptide that is recognized by the F-box protein beta-TRCP, whereas the other domain is composed of ovalicin. We show that MetAP-2 can be tethered to SCF(beta-TRCP), ubiquitinated, and degraded in a Protac-1-dependent manner. In the future, this approach may be useful for conditional inactivation of proteins, and for targeting disease-causing proteins for destruction.
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            Induced protein degradation: an emerging drug discovery paradigm

            Ashton C Lai, Craig M Crews (2016)
            Small-molecule drug discovery has traditionally focused on occupancy of a binding site that directly affects protein function. This article discusses emerging technologies, such as proteolysis-targeting chimaeras (PROTACs), that exploit cellular quality control machinery to selectively degrade target proteins, which could have advantages over traditional approaches, including the potential to target proteins that are not currently therapeutically tractable.
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              Induced pluripotent stem cells in disease modelling and drug discovery

              R. Rowe, George Daley (2019)
              The derivation of induced pluripotent stem cells (iPSCs) over a decade ago sparked widespread enthusiasm for the development of new models of human disease, enhanced platforms for drug discovery, and more widespread use of autologous cell-based therapy. Early studies using directed differentiation of iPSCs frequently uncovered cell-level phenotypes in monogenic diseases, but translation to tissue-level and organ-level diseases has required development of more complex, 3D, multicellular systems. Organoids and human–rodent chimaeras more accurately mirror the diverse cellular ecosystems of complex tissues and are being applied to iPSC disease models to recapitulate the pathobiology of a broad spectrum of human maladies, including infectious diseases, genetic disorders and cancer.
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                Author and article information

                Journal
                Journal ID (publisher-id): FDD
                Title: Future Drug Discovery
                Abbreviated Title: Future Drug. Discov.
                Abbreviated Title: Future Drug Discovery
                Publisher: Newlands Press Ltd (London, UK )
                ISSN (Electronic): 2631-3316
                Publication date (Electronic, pub): 13 March 2020
                Publication date (Electronic, collection): April 2020
                Volume: 2
                Issue: 2
                Electronic Location Identifier: FDD30
                Affiliations
                1Department of Pharmaceutical Sciences, University of Nebraska Medical Center, NE 68198, USA
                Author notes
                [* ]Author for correspondence: paul.trippier@ 123456unmc.edu
                Article
                DOI: 10.4155/fdd-2019-0037
                SO-VID: d4684dc3-b520-4a6f-aaa5-c62b09936462
                Copyright © © 2020 Paul Trippier
                License:

                This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License

                History
                Date received : 12 December 2019
                Date accepted : 21 January 2020
                Date: 13 March 2020
                Page count
                Pages: 3
                Categories
                Subject: Interview

                ScienceOpen disciplines: Biochemistry,Molecular medicine,Pharmaceutical chemistry,Bioinformatics & Computational biology,Biotechnology,Pharmacology & Pharmaceutical medicine
                Keywords: PROTACS,iPSC models,ALS,rare diseases,drug repurposing
                Data availability:
                ScienceOpen disciplines: Biochemistry, Molecular medicine, Pharmaceutical chemistry, Bioinformatics & Computational biology, Biotechnology, Pharmacology & Pharmaceutical medicine
                Keywords: PROTACS, iPSC models, ALS, rare diseases, drug repurposing

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