Chemical Modulation of the Human Oligopeptide Transporter 1, hPepT1

In humans, peptides derived from dietary proteins and peptide-like drugs are transported via the proton-dependent oligopeptide transporter hPepT1 (SLC15A1). hPepT1 is located across the apical membranes of the small intestine and kidney, where it serves as a high-capacity low-affinity transporter of a broad range of di- and tripeptides. hPepT1 is also overexpressed in the colon of inflammatory bowel disease (IBD) patients, where it mediates the transport of harmful peptides of bacterial origin. Therefore, hPepT1 is a drug target for prodrug substrates interacting with intracellular proteins or inhibitors blocking the transport of toxic bacterial products. In this study, we construct multiple structural models of hPepT1 representing different conformational states that occur during transport and inhibition. We then identify and characterize five ligands of hPepT1 using computational methods, such as virtual screening and QM-polarized ligand docking (QPLD), and experimental testing with uptake kinetic measurements and electrophysiological assays. Our results improve our understanding of the substrate and inhibitor specificity of hPepT1. Furthermore, the newly discovered ligands exhibit unique chemotypes, providing a framework for developing tool compounds with optimal intestinal absorption as well as future IBD therapeutics against this emerging drug target

Association between Glucocorticoid-Induced Osteoporosis and Myasthenia Gravis: A Cross-Sectional Study

<div><p>Purpose</p><p>To investigate the association between glucocorticoid-induced osteoporosis and myasthenia gravis (MG) using a cross-sectional survey in Japan.</p><p>Methods</p><p>We studied 363 patients with MG (female 68%; mean age, 57 ± 16 years) who were followed at six Japanese centers between April and July 2012. We evaluated the clinical information of MG and fractures, bone markers, and radiological assessment. Quality of life was measured using an MG-specific battery, MG-QOL15.</p><p>Results</p><p>Glucocorticoids were administered in 283 (78%) of 363 MG patients. Eighteen (6%) of 283 MG patients treated with prednisolone had a history of osteoporotic fractures. The duration of glucocorticoid therapy, but not the dose of prednisolone, was associated with the osteoporotic fractures in MG patients. Bone mineral density was significantly decreased in the MG patients with fractures. The multivariate analyses showed that the total quantitative MG score was the only independent factor associated with osteoporotic fractures (OR = 1.30, 95% CI 1.02–1.67, p = 0.03). MG patients who had experienced fractures reported more severe difficulties in activities of daily living.</p><p>Conclusion</p><p>Glucocorticoid-induced osteoporosis aggravates quality of life in patients with MG.</p></div

Quality of life was compared between myasthenia gravis (MG) patients with or without fractures using MG-QOL15 scores.

<p>The bar indicates the average.</p

Characteristics of 283 patients with myasthenia gravis (MG) treated with prednisolone

<p>*statistically significant</p><p>NTX, pyridinoline cross-linked amino-terminal telopeptide of type I collagen</p><p>BAP, bone isoform of alkaline phosphatase</p><p>Characteristics of 283 patients with myasthenia gravis (MG) treated with prednisolone</p

sj-docx-1-tan-10.1177_17562864241243186 – Supplemental material for Long-term safety and efficacy of zilucoplan in patients with generalized myasthenia gravis: interim analysis of the RAISE-XT open-label extension study

Supplemental material, sj-docx-1-tan-10.1177_17562864241243186 for Long-term safety and efficacy of zilucoplan in patients with generalized myasthenia gravis: interim analysis of the RAISE-XT open-label extension study by James F. Howard, Saskia Bresch, Constantine Farmakidis, Miriam Freimer, Angela Genge, Channa Hewamadduma, John Hinton, Yessar Hussain, Raul Juntas-Morales, Henry J. Kaminski, Angelina Maniaol, Renato Mantegazza, Masayuki Masuda, Richard J. Nowak, Kumaraswamy Sivakumar, Marek Śmiłowski, Kimiaki Utsugisawa, Tuan Vu, Michael D. Weiss, Małgorzata Zajda, Jos Bloemers, Babak Boroojerdi, Melissa Brock, Guillemette de la Borderie, Petra W. Duda, Mark Vanderkelen and M. Isabel Leite in Therapeutic Advances in Neurological Disorders</p