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991.
Structure–Activity Relationships of Benzenesulfonamide‐Based Inhibitors towards Carbonic Anhydrase Isoform Specificity 下载免费PDF全文
Avni Bhatt Dr. Brian P. Mahon Vinicius Wilian D. Cruzeiro Dr. Benedetta Cornelio Dr. Marie Laronze‐Cochard Dr. Mariangela Ceruso Prof. Dr. Janos Sapi Dr. Graham A. Rance Prof. Dr. Andrei N. Khlobystov Assoc. Prof. Dr. Antonella Fontana Prof. Dr. Adrian Roitberg Prof. Dr. Claudiu T. Supuran Prof. Dr. Robert McKenna 《Chembiochem : a European journal of chemical biology》2017,18(2):213-222
Carbonic anhydrases (CAs) are implicated in a wide range of diseases, including the upregulation of isoforms CA IX and XII in many aggressive cancers. However, effective inhibition of disease‐implicated CAs should minimally affect the ubiquitously expressed isoforms, including CA I and II, to improve directed distribution of the inhibitors to the cancer‐associated isoforms and reduce side effects. Four benzenesulfonamide‐based inhibitors were synthesized by using the tail approach and displayed nanomolar affinities for several CA isoforms. The crystal structures of the inhibitors bound to a CA IX mimic and CA II are presented. Further in silico modeling was performed with the inhibitors docked into CA I and XII to identify residues that contributed to or hindered their binding interactions. These structural studies demonstrated that active‐site residues lining the hydrophobic pocket, especially positions 92 and 131, dictate the positional binding and affinity of inhibitors, whereas the tail groups modulate CA isoform specificity. Geometry optimizations were performed on each ligand in the crystal structures and showed that the energetic penalties of the inhibitor conformations were negligible compared to the gains from active‐site interactions. These studies further our understanding of obtaining isoform specificity when designing small molecule CA inhibitors. 相似文献
992.
Design of S‐Allylcysteine in Situ Production and Incorporation Based on a Novel Pyrrolysyl‐tRNA Synthetase Variant 下载免费PDF全文
Dr. Matthias P. Exner Tilmann Kuenzl Tuyet Mai T. To Zhaofei Ouyang Sergej Schwagerus Michael G. Hoesl Prof. Dr. Christian P. R. Hackenberger Prof. Dr. Marga C. Lensen Prof. Dr. Sven Panke Prof. Dr. Nediljko Budisa 《Chembiochem : a European journal of chemical biology》2017,18(1):85-90
The noncanonical amino acid S‐allyl cysteine (Sac) is one of the major compounds of garlic extract and exhibits a range of biological activities. It is also a small bioorthogonal alkene tag capable of undergoing controlled chemical modifications, such as photoinduced thiol‐ene coupling or Pd‐mediated deprotection. Its small size guarantees minimal interference with protein structure and function. Here, we report a simple protocol efficiently to couple in‐situ semisynthetic biosynthesis of Sac and its incorporation into proteins in response to amber (UAG) stop codons. We exploited the exceptional malleability of pyrrolysyl‐tRNA synthetase (PylRS) and evolved an S‐allylcysteinyl‐tRNA synthetase (SacRS) capable of specifically accepting the small, polar amino acid instead of its long and bulky aliphatic natural substrate. We succeeded in generating a novel and inexpensive strategy for the incorporation of a functionally versatile amino acid. This will help in the conversion of orthogonal translation from a standard technique in academic research to industrial biotechnology. 相似文献
993.
Iterative Nonproteinogenic Residue Incorporation Yields α/β‐Peptides with a Helix–Loop–Helix Tertiary Structure and High Affinity for VEGF 下载免费PDF全文
Dr. James W. Checco Prof. Samuel H. Gellman 《Chembiochem : a European journal of chemical biology》2017,18(3):291-299
Inhibition of specific protein–protein interactions is attractive for a range of therapeutic applications, but the large and irregularly shaped contact surfaces involved in many such interactions make it challenging to design synthetic antagonists. Here, we describe the development of backbone‐modified peptides containing both α‐ and β‐amino acid residues (α/β‐peptides) that target the receptor‐binding surface of vascular endothelial growth factor (VEGF). Our approach is based on the Z‐domain, which adopts a three‐helix bundle tertiary structure. We show how a two‐helix “mini‐Z‐domain” can be modified to contain β and other nonproteinogenic residues while retaining the target‐binding epitope by using iterative unnatural residue incorporation. The resulting α/β‐peptides are less susceptible to proteolysis than is their parent α‐peptide, and some of these α/β‐peptides match the full‐length Z‐domain in terms of affinity for receptor‐recognition surfaces on the VEGF homodimer. 相似文献
994.
995.
Different Enzymatic Processing of γ‐Phosphoramidate and γ‐Phosphoester‐Modified ATP Analogues 下载免费PDF全文
Susanne Ermert Dr. Stephan M. Hacker Dr. Alexander Buntru Prof. Dr. Martin Scheffner Prof. Dr. Christof R. Hauck Prof. Dr. Andreas Marx 《Chembiochem : a European journal of chemical biology》2017,18(4):378-381
Monitoring the activity of ATP‐consuming enzymes provides the basis for elucidating their modes of action and regulation. Although a number of ATP analogues have been developed for this, their scope is restricted because of the limited acceptance by respective enzymes. In order to clarify which kind of phosphate‐modified ATP analogues are accepted by the α‐β‐phosphoanhydride‐cleaving ubiquitin‐activating enzyme 1 (UBA1) and the β‐γ‐phosphoanhydride‐cleaving focal adhesion kinase (FAK), we tested phosphoramidate‐ and phosphoester‐modified ATP analogues. UBA1 and FAK were able to convert phosphoramidate‐modified ATP analogues, even with a bulky modification like biotin. In contrast, a phosphoester‐modified analogue was poorly accepted. These results demonstrate that minor variations in the design of ATP analogues for monitoring ATP utilization have a significant impact on enzymatic acceptance. 相似文献
996.
Dr. Riccardo Martini Dr. Francesca Esposito Dr. Angela Corona Dr. Roberto Ferrarese Dr. Elisa Rita Ceresola Dr. Laura Visconti Dr. Cristina Tintori Dr. Alessandro Barbieri Dr. Andrea Calcaterra Dr. Valentina Iovine Dr. Filippo Canducci Prof. Enzo Tramontano Prof. Maurizio Botta 《Chembiochem : a European journal of chemical biology》2017,18(4):374-377
997.
998.
Dr. Christina Haußner Dominik Damm Sandra Nirschl Anette Rohrhofer Prof. Dr. Barbara Schmidt Prof. Dr. Jutta Eichler 《Chembiochem : a European journal of chemical biology》2017,18(7):647-653
The broadly neutralizing HIV‐1 antibody b12 recognizes the CD4 binding site of the HIV‐1 envelope glycoprotein gp120 and efficiently neutralizes HIV‐1 infections in vitro and in vivo. Based on the 3D structure of a b12 ? gp120 complex, we have designed an assembled peptide (b12‐M) that presents the parts of the three heavy‐chain complementarity‐determining regions (CDRs) of b12, which contain the contact sites of the antibody for gp120. This b12‐mimetic peptide, as well as a truncated peptide presenting only two of the three heavy‐chain CDRs of b12, were shown to recognize gp120 in a similar manner to b12, as well as to inhibit HIV‐1 infection, demonstrating functional mimicry of b12 by the paratope mimetic peptides. 相似文献
999.
Synthesis,Characterization and Immunological Evaluation of Self‐Adjuvanting Group A Streptococcal Vaccine Candidates Bearing Various Lipidic Adjuvanting Moieties 下载免费PDF全文
Dr. Vincent Fagan Dr. Waleed M. Hussein Mei Su Ashwini K. Giddam Dr. Michael R. Batzloff Prof. Michael F. Good Prof. Istvan Toth Dr. Pavla Simerska 《Chembiochem : a European journal of chemical biology》2017,18(6):545-553
Four group A streptococcal glycolipopeptide vaccine candidates with different lipidic adjuvanting moieties were prepared and characterized. The immunogenicity of the compounds was evaluated by macrophage and dendritic cell uptake studies and by in vivo quantification of systemic IgG antibody by ELISA. Three of the candidates showed significant induction of the IgG response. 相似文献
1000.
Nancy E. Martinez Dr. Tobias J. Zimmermann Christian Goosmann Dr. Tobias Alexander Prof. Dr. Christian Hedberg Dr. Slava Ziegler Prof. Dr. Arturo Zychlinsky Prof. Dr. Dr. Herbert Waldmann 《Chembiochem : a European journal of chemical biology》2017,18(10):888-893
Neutrophils are short‐lived leukocytes that migrate to sites of infection as part of the acute immune response, where they phagocytose, degranulate, and form neutrophil extracellular traps (NETs). During NET formation, the nuclear lobules of neutrophils disappear and the chromatin expands and, accessorized with neutrophilic granule proteins, is expelled. NETs can be pathogenic in, for example, sepsis, cancer, and autoimmune and cardiovascular diseases. Therefore, the identification of inhibitors of NET formation is of great interest. Screening of a focused library of natural‐product‐inspired compounds by using a previously validated phenotypic NET assay identified a group of tetrahydroisoquinolines as new NET formation inhibitors. This compound class opens up new avenues for the study of cellular death through NET formation (NETosis) at different stages, and might inspire new medicinal chemistry programs aimed at NET‐dependent diseases. 相似文献