Granulocyte-macrophage colony stimulating factor (GM-CSF) activity has been linked to pro-inflammatory effects in autoimmune syndromes, such as rheumatoid arthritis. Thus GM-CSF mimetics with antagonist activity might play a therapeutic role in these diseases. The human GM-CSF core structure consists of a four alpha-helix bundle, and GM-CSF activity is controlled by its binding to a two-subunit receptor. A number of residues located on the B and C helices of GM-CSF are postulated to interact with the alpha chain of the GM-CSF receptor (GM-CSFR). Several approaches have been successfully utilized to develop peptide mimetics of this site, including peptides from the native sequence, a peptide derived from a recombinant antibody (rAb) light chain which mimicked GM-CSF receptor binding activity, and structurally guided de novo design. Analysis of the rAb light chain had suggested mimicry of GM-CSF with residues mostly contributed by the CDR I region. Key residues involved in CDR I peptide/GM-CSFR binding were identified by truncation and alteration of individual residues, while the structural elements required to antagonize the biological action of GM-CSF were separately tested in binding and inhibitory activity assays of multiple cyclic analogues. A peptide designed to retain the loop conformation of the CDR I region of the rAb light chain competed with GM-CSF for both antibody and receptor binding, but the role of specific residues in antibody versus receptor binding differed markedly. These studies suggest that structural analysis of peptide mimetics can reveal differences in receptor and antibody binding, perhaps including key interactions that impact binding kinetics. Peptide mimetics of other four-helix bundle cytokines are reviewed, including helical and reverse turn mimetics of helical structures. Use of peptide mimetics coupled with structural and kinetic analysis provides a powerful approach to identifying important receptor-ligand interactions, which implications for rational design of novel therapeutics.
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http://dx.doi.org/10.2174/1381612023393198 | DOI Listing |
Langmuir
January 2025
Faculty of Science, Yamagata University, 1-4-12, Kojirakawa, Yamagata 990-8560, Japan.
The aggregation and accumulation of amyloid β 42 (Aβ42) peptides on the surface of brain cells is associated with Alzheimer's disease (AD); however, the underlying molecular mechanisms remain unclear. Herein, we used a unique brain-mimetic open system that continuously flows Aβ42 solution to analyze the initial aggregation and adsorptive nature of Aβ42 at physiological concentrations on the lipid membrane. The open system accelerated the adsorption and dimerization kinetics.
View Article and Find Full Text PDFNaunyn Schmiedebergs Arch Pharmacol
January 2025
Institute of Pharmacy, Nirma University, Gujarat, 382481, India.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) discovery has added a new paradigm to our understanding of cholesterol homeostasis and lipid metabolism. Since its discovery, PCSK9 inhibitors have become a widely investigated therapeutic class for lipid management in cardiovascular diseases and hypercholesterolemia. Scientists have explored different approaches for PCSK9 inhibition, such as monoclonal antibodies (mAbs), gene silencing and gene editing techniques, vaccines, mimetic peptides, and small molecules.
View Article and Find Full Text PDFRSC Med Chem
December 2024
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research Sector 67, S. A. S. Nagar Punjab 160062 India
Aberrant protein misfolding and accumulation is considered to be a major pathological pillar of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Aggregation of amyloid-β (Aβ) peptide leads to the formation of toxic amyloid fibrils and is associated with cognitive dysfunction and memory loss in Alzheimer's disease (AD). Designing molecules that inhibit amyloid aggregation seems to be a rational approach to AD drug development.
View Article and Find Full Text PDFKidney Med
February 2025
Department of Nephrology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Pure red cell aplasia (PRCA) is a rare complication of erythropoietin (EPO) therapy, characterized by a severe deficiency in red blood cell production. There is no guideline on the treatment for PRCA because there have been too few cases to perform prospective cohort studies. The main treatments for PRCA include immediate cessation of EPO, restrictive transfusion, and immunosuppressive therapies.
View Article and Find Full Text PDFLife Metab
October 2024
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Current treatment paradigms for metabolic dysfunction-associated steatohepatitis (MASH) are based primarily on dietary restrictions and the use of existing drugs, including anti-diabetic and anti-obesity medications. Given the limited number of approved drugs specifically for MASH, recent efforts have focused on promising strategies that specifically target hepatic lipid metabolism, inflammation, fibrosis, or a combination of these processes. In this review, we examined the pathophysiology underlying the development of MASH in relation to recent advances in effective MASH therapy.
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