Inhibitors of dermatan sulfate epimerase 1 decreased accumulation of glycosaminoglycans in mucopolysaccharidosis type I fibroblasts.

Genetic deficiency of alpha-L-iduronidase causes mucopolysaccharidosis type I (MPS-I) disease, due to accumulation of glycosaminoglycans (GAGs) including chondroitin/dermatan sulfate (CS/DS) and heparan sulfate (HS) in cells. Currently, patients are treated by infusion of recombinant iduronidase or by hematopoietic stem cell transplantation. An alternative approach is to reduce the L-iduronidase substrate, through limiting the biosynthesis of iduronic acid. Our earlier study demonstrated that ebselen attenuated GAGs accumulation in MPS-I cells, through inhibiting iduronic acid producing enzymes. However, ebselen has multiple pharmacological effects, which prevents its application for MPS-I. Thus, we continued the study by looking for novel inhibitors of dermatan sulfate epimerase 1 (DS-epi1), the main responsible enzyme for production of iduronic acid in CS/DS chains. Based on virtual screening of chemicals towards chondroitinase AC, we constructed a library with 1,064 compounds that were tested for DS-epi1 inhibition. Seventeen compounds were identified to be able to inhibit 27%-86% of DS-epi1 activity at 10 µM. Two compounds were selected for further investigation based on the structure properties. The results show that both inhibitors had a comparable level in inhibition of DS-epi1while they had negligible effect on HS epimerase. The two inhibitors were able to reduce iduronic acid biosynthesis in CS/DS and GAG accumulation in WT and MPS-I fibroblasts. Docking of the inhibitors into DS-epi1 structure shows high affinity binding of both compounds to the active site. The collected data indicate that these hit compounds may be further elaborated to a potential lead drug used for attenuation of GAGs accumulation in MPS-I patients.

Gasto energético na marcha em pacientes com mucopolissacaridose / Energy expenditure during gait in patients with mucopolysaccharidosis

Objetivo: Avaliar o gasto energético na marcha em pacientes com mucopolissacaridose, utilizando uma metodologia simples e aplicável ao ambiente clínico. Métodos: realizou-se estudo transversal comparando-se o gasto energético da marcha de 19 pacientes portadores de mucopolissacaridose (Grupo MPS) com 19 indivíduos assintomáticos da comunidade (Grupo Comparação). O gasto energético foi mensurado em Cal por um relógio da marca Polar (modelo FT7) durante uma caminhada de 50 metros. Foram também avaliados idade, peso, altura, IMC, frequência cardíaca inicial, frequência cardíaca final, e tempo de marcha. Resultados: O Grupo MPS teve gasto energético na marcha de 2,84 Cal(±1,01), versus 1,42 Cal(±0,51), sendo 100% maior que o Grupo Comparação; também em relação ao Grupo Comparação, o Grupo MPS teve frequência cardíaca inicial 22% maior, frequência cardíaca final 13% e tempo da caminhada 25% maiores. Conclusões: o gasto energético na marcha de pacientes com mucopolissacaridose é duas vezes mais alto em comparação com indivíduos assintomáticos e a metodologia usada para avaliação mostrou-se alternativa eficiente para o ambiente clínico convencional. Nível de Evidencia III, Estudo Transversal Comparativo.

Objective: The aim of this study is to evaluate energy expenditure during gait in patients with mucopolysaccharidosis using a simple methodology applicable to the clinical setting. Methods: a cross-sectional study was carried out comparing energy expenditure during gait in 19 patients with mucopolysaccharidosis (MPS Group) with 19 control individuals from the community (Comparison Group). Energy expenditure was measured in calories using a Polar telemetric watch (model FT7) in a 50-meters walking. Variables such as age, weight, height, BMI, initial hart rate, final hart rate, and gait time were recorded. Results: MPS Group showed an expenditure during gait of 2.84 Cal (± 1.01) versus 1.42 Cal (± 0.51), being 100% higher than the Comparison Group; MPS Group had also increased initial hart rate (22% higher), final hart rate (13% higher), and time waking (13% faster). Conclusions: energy expenditure during gait in MPS patients was twice higher compared to control individuals and the methodology for evaluation proved an efficient alternative to conventional clinical setting. Evidence Level III, Cross-sectional Comparative Study.