Design, Synthesis and Evaluation of AdSS Bisubstrate Inhibitors

ChemMedChem ◽  
2020 ◽  
Vol 15 (23) ◽  
pp. 2269-2272
Author(s):  
Nidhi Tibrewal ◽  
Gregory I. Elliott
Keyword(s):  
Design Synthesis ◽  
Bisubstrate Inhibitors

scholarly journals Structure-Based Design, Synthesis, and in vitro Evaluation of Bisubstrate Inhibitors for CatecholO-Methyltransferase (COMT)

2000 ◽  
Vol 6 (6) ◽  
pp. 971-982 ◽  
Author(s):  
Birgit Masjost ◽  
Patrick Ballmer ◽  
Edilio Borroni ◽  
Gerhard Zürcher ◽  
Fritz K. Winkler ◽  
...  
Keyword(s):  
Design Synthesis ◽  
In Vitro Evaluation ◽  
Bisubstrate Inhibitors

scholarly journals Chemoproteomic study uncovers HemK2/KMT9 as a new target for NTMT1 bisubstrate inhibitors

2021 ◽  
Author(s):  
Dongxing Chen ◽  
Ying Meng ◽  
Dan Yu ◽  
Nicholas Noinaj ◽  
Xiaodong Cheng ◽  
...  
Keyword(s):  
Rational Design ◽  
Biochemical Characterization ◽  
Potent Inhibitor ◽  
Protein Networks ◽  
Selective Inhibitors ◽  
Chemical Probe ◽  
Design Synthesis ◽  
Bisubstrate Inhibitors ◽  
Methyltransferase 1

Understanding the selectivity of methyltransferase inhibitors is important to dissect the functions of each methyltransferase target. From this perspective, here we report a chemoproteomic study to profile the selectivity of a potent protein N-terminal methyltransferase 1 (NTMT1) bisubstrate inhibitor NAH-C3-GPKK (Ki, app = 7 nM) in endogenous proteomes. First, we describe the rational design, synthesis, and biochemical characterization of a new chemical probe 6, a biotinylated analogue of NAH-C3-GPKK. Next, we systematically analyze protein networks that may selectively interact with the biotinylated probe 6 in concert with the competitor NAH-C3-GPKK. Besides NTMT1, the designated NTMT1 bisubstrate inhibitor NAH-C3-GPKK was found to also potently inhibit a methyltransferase complex HemK2-Trm112 (also known as KMT9-Trm112), highlighting the importance of systematic selectivity profiling. Furthermore, this is the first potent inhibitor for HemK2/KMT9 reported to date. Thus, our studies lay the foundation for future efforts towards the development of selective inhibitors for NTMT1 and HemK2/KMT9.

Self-Assembly of Hydrogels From Elastin-Mimetic Block Copolymers

2002 ◽  
Vol 724 ◽  
Author(s):  
Elizabeth R. Wright ◽  
R. Andrew McMillan ◽  
Alan Cooper ◽  
Robert P. Apkarian ◽  
Vincent P. Conticello
Keyword(s):  
Block Copolymers ◽  
Self Assembly ◽  
Triblock Copolymers ◽  
Variable Temperature ◽  
Inverse Temperature ◽  
Temperature Transition ◽  
Scanning Calorimetry ◽  
Design Synthesis ◽  
Inverse Temperature Transition ◽  
Functional Biomaterials

AbstractTriblock copolymers have traditionally been synthesized with conventional organic components. However, triblock copolymers could be synthesized by the incorporation of two incompatible protein-based polymers. The polypeptides would differ in their hydrophobicity and confer unique physiochemical properties to the resultant materials. One protein-based polymer, based on a sequence of native elastin, that has been utilized in the synthesis of biomaterials is poly (Valine-Proline-Glycine-ValineGlycine) or poly(VPGVG) [1]. This polypeptide has been shown to have an inverse temperature transition that can be adjusted by non-conservative amino acid substitutions in the fourth position [2]. By combining polypeptide blocks with different inverse temperature transition values due to hydrophobicity differences, we expect to produce amphiphilic polypeptides capable of self-assembly into hydrogels. Our research examines the design, synthesis and characterization of elastin-mimetic block copolymers as functional biomaterials. The methods that are used for the characterization include variable temperature 1D and 2D High-Resolution-NMR, cryo-High Resolutions Scanning Electron Microscopy and Differential Scanning Calorimetry.

Discovery of Antibacterial Agents Inhibiting the Energy-Coupling Factor (ECF) Transporters by Structure-Based Virtual Screening

2020 ◽  
Author(s):  
Eleonora Diamanti ◽  
Inda Setyawati ◽  
Spyridon Bousis ◽  
leticia mojas ◽  
lotteke Swier ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Antibacterial Agents ◽  
Antimicrobial Agents ◽  
Energy Coupling ◽  
Coupling Factor ◽  
Design Synthesis ◽  
Screening Design ◽  
Starting Point ◽  
Wide Range ◽  
Vitamin Uptake

Here, we report on the virtual screening, design, synthesis and structure–activity relationships (SARs) of the first class of selective, antibacterial agents against the energy-coupling factor (ECF) transporters. The ECF transporters are a family of transmembrane proteins involved in the uptake of vitamins in a wide range of bacteria. Inhibition of the activity of these proteins could reduce the viability of pathogens that depend on vitamin uptake. Because of their central role in the metabolism of bacteria and their absence in humans, ECF transporters are novel potential antimicrobial targets to tackle infection. The hit compound’s metabolic and plasma stability, the potency (20, MIC Streptococcus pneumoniae = 2 µg/mL), the absence of cytotoxicity and a lack of resistance development under the conditions tested here suggest that this scaffold may represent a promising starting point for the development of novel antimicrobial agents with an unprecedented mechanism of action.<br>

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