686276-33-5Relevant academic research and scientific papers
Dynamics Determine Signaling in a Multicomponent System Associated with Rheumatoid Arthritis
Lindgren, Cecilia,Tyagi, Mohit,Viljanen, Johan,Toms, Johannes,Ge, Changrong,Zhang, Naru,Holmdahl, Rikard,Kihlberg, Jan,Linusson, Anna
, p. 4774 - 4790 (2018)
Strategies that target multiple components are usually required for treatment of diseases originating from complex biological systems. The multicomponent system consisting of the DR4 major histocompatibility complex type II molecule, the glycopeptide CII259-273 from type II collagen, and a T-cell receptor is associated with development of rheumatoid arthritis (RA). We introduced non-native amino acids and amide bond isosteres into CII259-273 and investigated the effect on binding to DR4 and the subsequent T-cell response. Molecular dynamics simulations revealed that complexes between DR4 and derivatives of CII259-273 were highly dynamic. Signaling in the overall multicomponent system was found to depend on formation of an appropriate number of dynamic intramolecular hydrogen bonds between DR4 and CII259-273, together with the positioning of the galactose moiety of CII259-273 in the DR4 binding groove. Interestingly, the system tolerated modifications at several positions in CII259-273, indicating opportunities to use analogues to increase our understanding of how rheumatoid arthritis develops and for evaluation as vaccines to treat RA.
Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 2. Peptide structure- activity studies
Dragovich, Peter S.,Webber, Stephen E.,Babine, Robert E.,Fuhrman, Sheila A.,Patick, Amy K.,Matthews, David A.,Reich, Siegfried H.,Marakovits, Joseph T.,Prins, Thomas J.,Zhou, Ru,Tikhe, Jayashree,Littlefield, Ethel S.,Bleckman, Ted M.,Wallace, Michael B.,Little, Thomas L.,Ford, Clifford E.,Meador III, James W.,Ferre, Rose Ann,Brown, Edward L.,Binford, Susan L.,DeLisle, Dorothy M.,Worland, Stephen T.
, p. 2819 - 2834 (2007/10/03)
The structure-based design, chemical synthesis, and biological evaluation of various peptidederived human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of an ethyl propenoate Michael acceptor moiety and a tripeptidyl binding determinant. The systematic modification of each amino acid residue present in the binding determinant as well as the N-terminal functionality is described. Such modifications are shown to provide irreversible HRV-14 3CP inhibitors with anti-3CP activities (k(obs)/[I]) ranging from 60 to 280 000 M-1 s-1 and antiviral EC50's which approach 0.15 μM. An optimized inhibitor which incorporates several improvements identified by the structure-activity studies is also described. This molecule displays very rapid irreversible inhibition of HRV-14 3CP (k(obs)/[I] = 800 000 M-1 s-1) and potent antiviral activity against HRV-14 in cell culture (EC50 = 0.056 μM). A 1.9 A? crystal structure of an S-alkylthiocarbamate-containing inhibitor complexed with HRV-2 3CP is also detailed.
