Structure–Activity Relationship in Pyrazolo[4,3-<i>c</i>]pyridines, First Inhibitors of PEX14–PEX5 Protein–Protein Interaction with Trypanocidal Activity

Dawidowski, Maciej; Kalel, Vishal C.; Napolitano, Valeria; Fino, Roberto; Schorpp, Kenji; Emmanouilidis, Leonidas; Lenhart, Dominik; Ostertag, Michael; Kaiser, Marcel; Kolonko, Marta; Tippler, Bettina; Schliebs, Wolfgang; Dubin, Grzegorz; Mäser, Pascal; Tetko, Igor V.; Hadian, Kamyar; Plettenburg, Oliver; Erdmann, Ralf; Sattler, Michael; Popowicz, Grzegorz M.

doi:10.1021/acs.jmedchem.9b01876

Cited by 18 publications

(26 citation statements)

References 67 publications

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“…Inhibition of glycosomal compartmentation affects several essential metabolic pathways and thus provides an attractive drug target. We previously developed small-molecule inhibitors of PEX14–PEX5 PPI that block glycosomal matrix protein import and kill T. brucei parasites ( Dawidowski et al, 2017 , 2020 ). These inhibitors also showed therapeutic efficacy upon oral delivery in animal models of infection ( Dawidowski et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Novel Trypanocidal Inhibitors that Block Glycosome Biogenesis by Targeting PEX3–PEX19 Interaction

Li¹,

Gaussmann²,

Tippler³

et al. 2021

Front. Cell Dev. Biol.

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Human pathogenic trypanosomatid parasites harbor a unique form of peroxisomes termed glycosomes that are essential for parasite viability. We and others previously identified and characterized the essential Trypanosoma brucei ortholog TbPEX3, which is the membrane-docking factor for the cytosolic receptor PEX19 bound to the glycosomal membrane proteins. Knockdown of TbPEX3 expression leads to mislocalization of glycosomal membrane and matrix proteins, and subsequent cell death. As an early step in glycosome biogenesis, the PEX3–PEX19 interaction is an attractive drug target. We established a high-throughput assay for TbPEX3–TbPEX19 interaction and screened a compound library for small-molecule inhibitors. Hits from the screen were further validated using an in vitro ELISA assay. We identified three compounds, which exhibit significant trypanocidal activity but show no apparent toxicity to human cells. Furthermore, we show that these compounds lead to mislocalization of glycosomal proteins, which is toxic to the trypanosomes. Moreover, NMR-based experiments indicate that the inhibitors bind to PEX3. The inhibitors interfering with glycosomal biogenesis by targeting the TbPEX3–TbPEX19 interaction serve as starting points for further optimization and anti-trypanosomal drug development.

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Section: Discussionmentioning

confidence: 99%

Novel Trypanocidal Inhibitors that Block Glycosome Biogenesis by Targeting PEX3–PEX19 Interaction

Li¹,

Gaussmann²,

Tippler³

et al. 2021

Front. Cell Dev. Biol.

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“…We trained the CATS algorithm with the structure of the most active compound in respect to its trypanocidal activity of the SAR library of PEX14 inhibitors . The output consisted of a library of roughly 10 000 molecules structurally similar to the template structure, selected by the algorithm from an in silico library of approximately 14.5 million purchasable molecules.…”

Section: Methodsmentioning

confidence: 99%

Computer-Aided Design and Synthesis of a New Class of PEX14 Inhibitors: Substituted 2,3,4,5-Tetrahydrobenzo[F][1,4]oxazepines as Potential New Trypanocidal Agents

Fino

Lenhart

Kalel

et al. 2021

J. Chem. Inf. Model.

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African and American trypanosomiases are estimated to affect several million people across the world, with effective treatments distinctly lacking. New, ideally oral, treatments with higher efficacy against these diseases are desperately needed. Peroxisomal import matrix (PEX) proteins represent a very interesting target for structure-and ligand-based drug design. The PEX5−PEX14 protein−protein interface in particular has been highlighted as a target, with inhibitors shown to disrupt essential cell processes in trypanosomes, leading to cell death. In this work, we present a drug development campaign that utilizes the synergy between structural biology, computer-aided drug design, and medicinal chemistry in the quest to discover and develop new potential compounds to treat trypanosomiasis by targeting the PEX14−PEX5 interaction. Using the structure of the known lead compounds discovered by Dawidowski et al. as the template for a chemically advanced template search (CATS) algorithm, we performed scaffold-hopping to obtain a new class of compounds with trypanocidal activity, based on 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepines chemistry. The initial compounds obtained were taken forward to a first round of hit-to-lead optimization by synthesis of derivatives, which show activities in the range of low-to high-digit micromolar IC 50 in the in vitro tests. The NMR measurements confirm binding to PEX14 in solution, while immunofluorescent microscopy indicates disruption of protein import into the glycosomes, indicating that the PEX14−PEX5 protein−protein interface was successfully disrupted. These studies result in development of a novel scaffold for future lead optimization, while ADME testing gives an indication of further areas of improvement in the path from lead molecules toward a new drug active against trypanosomes.

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“…O benznidazol é o medicamento de primeira escolha para ser utilizado na terapia da doença durante a fase aguda, sendo mais tolerado por longos períodos de tempo, possui uma meia vida de eliminação entre dez e treze horas, sua biodisponibilidade oral chega a ser maior que 90%, atua diminuindo a capacidade de replicação do parasita por meio da interação química covalente com moléculas, dentre elas o DNA do Trypanosoma cruzi (Dawidowski et al, 2020).…”

Section: Tratamento Farmacológico Atualunclassified

Doenças negligenciadas e indústria farmacêutica: o caso da Doença de Chagas

Silva

Dantas

Silva

et al. 2021

RSD

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O desenvolvimento de novos fármacos, no contexto das Doenças Tropicais Negligenciadas (DTNs), permanece como um grande desafio. Dentre as DTNs, destaca-se a Doença de Chagas (DC), a qual possui elevada morbimortalidade. Assim, este estudo objetiva resgatar informações acerca do cenário atual, bem como novas estratégias e inovações no tratamento farmacológico da DC. Para tal, foi realizada uma revisão narrativa, em que foram selecionados artigos no PubMed, SciELO e LILACS, no período entre 2015 e 2020. Buscando avaliar a relevância no meio acadêmico, comparou-se o número de publicações no SciELO entre 1950 e 2019, sobre DC, diabetes mellitus e câncer. Também se buscou informações sobre ensaios clínicos no site ClinicalTrials.gov. Nos últimos 20 anos, o número de publicações sobre a DC no SciELO foi bastante inferior se comparado com diabetes mellitus e câncer. Ademais, apenas dois medicamentos estão disponíveis, sendo eles benznidazol e nifurtimox, os quais possuem limitações como a quantidade de efeitos adversos. Por isso, novas opções terapêuticas (grânulos, sistemas multiparticulados, etc) têm sido estudadas, principalmente no caso do benznidazol, tendo demonstrado resultados promissores quanto à otimização de toxicidade, absorção e biodisponibilidade, por exemplo. Quanto aos ensaios clínicos, foi encontrado um total de sete estudos, os quais investigam cinco compostos para o tratamento da DC. Somente um dos compostos não tem uso clínico já registrado, o selênio, o que sugere uma deficiência na busca por novos candidatos à fármacos. Tais informações reforçam, portanto, o caráter negligenciado da DC, bem como enfatizam a importância de pesquisar novas terapias para esta parasitose.

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Structure–Activity Relationship in Pyrazolo[4,3-c]pyridines, First Inhibitors of PEX14–PEX5 Protein–Protein Interaction with Trypanocidal Activity

Cited by 18 publications

References 67 publications

Novel Trypanocidal Inhibitors that Block Glycosome Biogenesis by Targeting PEX3–PEX19 Interaction

Novel Trypanocidal Inhibitors that Block Glycosome Biogenesis by Targeting PEX3–PEX19 Interaction

Computer-Aided Design and Synthesis of a New Class of PEX14 Inhibitors: Substituted 2,3,4,5-Tetrahydrobenzo[F][1,4]oxazepines as Potential New Trypanocidal Agents

Doenças negligenciadas e indústria farmacêutica: o caso da Doença de Chagas

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