Search

Your search keyword '"Christopher J. Farady"' showing total 2 results
Start Over Author "Christopher J. Farady" Journal bioorganic & medicinal chemistry letters
2 results on '"Christopher J. Farady"'

1. Structure-based design and synthesis of macrocyclic human rhinovirus 3C protease inhibitors

Author

Simone Schleeger, Stephanie C. Paulding, Lori Andrews, Ryann E. Swale, Frederic Villard, Christopher J. Farady, Holger Sellner, Kenji Namoto, Robert J. Moreau, Michael Robinson, Finton Sirockin, Christian Wiesmann, Joachim Loup, Kathrin Schipp, and E. Valeur

Subjects
Models, Molecular, 0301 basic medicine, Macrocyclic Compounds, Rhinovirus, Stereochemistry, 030106 microbiology, Clinical Biochemistry, Molecular Conformation, Pharmaceutical Science, Microbial Sensitivity Tests, Cysteine Proteinase Inhibitors, Crystallography, X-Ray, medicine.disease_cause, Antiviral Agents, Biochemistry, Structure-Activity Relationship, Viral Proteins, 03 medical and health sciences, Solid-phase synthesis, Drug Discovery, Hydrolase, medicine, Humans, 3c protease, Molecular Biology, Dose-Response Relationship, Drug, Chemistry, Organic Chemistry, 3C Viral Proteases, Cysteine Endopeptidases, 030104 developmental biology, Drug Design, Molecular Medicine, Structure based
Abstract

The design and synthesis of macrocyclic inhibitors of human rhinovirus 3C protease is described. A macrocyclic linkage of the P1 and P3 residues, and the subsequent structure-based optimization of the macrocycle conformation and size led to the identification of a potent biochemical inhibitor 10 with sub-micromolar antiviral activity.

Published
2018

2. Improving the species cross-reactivity of an antibody using computational design

Author

Christopher J. Farady, Charles S. Craik, Benjamin D. Sellers, and Matthew P. Jacobson

Subjects
Serine Proteinase Inhibitors, medicine.drug_class, In silico, Clinical Biochemistry, Pharmaceutical Science, Cross Reactions, Protein Engineering, Monoclonal antibody, medicine.disease_cause, Biochemistry, Cross-reactivity, Antibodies, Article, Mice, Species Specificity, Antigen, Drug Discovery, medicine, Animals, Humans, Molecular Biology, Serine protease, biology, Chemistry, Serine Endopeptidases, Organic Chemistry, Computational Biology, Membrane Proteins, Protein engineering, In vitro, Protein Structure, Tertiary, Amino Acid Substitution, Drug Design, Mutation, biology.protein, Thermodynamics, Molecular Medicine, Antibody
Abstract

The high degree of specificity displayed by antibodies often results in varying potencies against antigen orthologs, which can affect the efficacy of these molecules in different animal models of disease. We have used a computational design strategy to improve the species cross-reactivity of an antibody-based inhibitor of the cancer-associated serine protease MT-SP1. In silico predictions were tested in vitro, and the most effective mutation, T98R, was shown to improve antibody affinity for the mouse ortholog of the enzyme 14-fold, resulting in an inhibitor with a K(I) of 340 pM. This improved affinity will be valuable when exploring the role of MT-SP1 in mouse models of cancer, and the strategy outlined here could be useful in fine-tuning antibody specificity.

Published
2009

Catalog

Books, media, physical & digital resources
See catalog results