81378-80-5Relevant academic research and scientific papers
Targeting the Main Protease of SARS-CoV-2: From the Establishment of High Throughput Screening to the Design of Tailored Inhibitors
Breidenbach, Julian,Lemke, Carina,Pillaiyar, Thanigaimalai,Sch?kel, Laura,Al Hamwi, Ghazl,Diett, Miriam,Gedschold, Robin,Geiger, Nina,Lopez, Vittoria,Mirza, Salahuddin,Namasivayam, Vigneshwaran,Schiedel, Anke C.,Sylvester, Katharina,Thimm, Dominik,Vielmuth, Christin,Phuong Vu, Lan,Zyulina, Maria,Bodem, Jochen,Gütschow, Michael,Müller, Christa E.
supporting information, p. 10423 - 10429 (2021/04/29)
The main protease of SARS-CoV-2 (Mpro), the causative agent of COVID-19, constitutes a significant drug target. A new fluorogenic substrate was kinetically compared to an internally quenched fluorescent peptide and shown to be ideally suitable for high throughput screening with recombinantly expressed Mpro. Two classes of protease inhibitors, azanitriles and pyridyl esters, were identified, optimized and subjected to in-depth biochemical characterization. Tailored peptides equipped with the unique azanitrile warhead exhibited concomitant inhibition of Mpro and cathepsin L, a protease relevant for viral cell entry. Pyridyl indole esters were analyzed by a positional scanning. Our focused approach towards Mpro inhibitors proved to be superior to virtual screening. With two irreversible inhibitors, azanitrile 8 (kinac/Ki=37 500 m?1 s?1, Ki=24.0 nm) and pyridyl ester 17 (kinac/Ki=29 100 m?1 s?1, Ki=10.0 nm), promising drug candidates for further development have been discovered.
Design, synthesis and biological evaluation of potent azadipeptide nitrile inhibitors and activity-based probes as promising anti-Trypanosoma brucei agents
Yang, Peng-Yu,Wang, Min,Li, Lin,Wu, Hao,He, Cynthia Y.,Yao, Shao Q.
supporting information; experimental part, p. 6528 - 6541 (2012/07/13)
Trypanosoma cruzi and Trypanosoma brucei are parasites that cause Chagas disease and African sleeping sickness, respectively. There is an urgent need for the development of new drugs against both diseases due to the lack of adequate cures and emerging drug resistance. One promising strategy for the discovery of small-molecule therapeutics against parasitic diseases has been to target the major cysteine proteases such as cruzain for T. cruzi, and rhodesain/TbCatB for T. brucei. Azadipeptide nitriles belong to a novel class of extremely potent cysteine protease inhibitors against papain-like proteases. We herein report the design, synthesis, and evaluation of a series of azanitrile-containing compounds, most of which were shown to potently inhibit both recombinant cruzain and rhodesain at low nanomolar/picomolar ranges. A strong correlation between the potency of rhodesain inhibition (i.e., target-based screening) and trypanocidal activity (i.e., whole-organism-based screening) of the compounds was observed. To facilitate detailed studies of this important class of inhibitors, selected hit compounds from our screenings were chemically converted into activity-based probes (ABPs), which were subsequently used for in situ proteome profiling and cellular localization studies to further elucidate potential cellular targets (on and off) in both the disease-relevant bloodstream form (BSF) and the insect-residing procyclic form (PCF) of Trypanosoma brucei. Overall, the inhibitors presented herein show great promise as a new class of anti-trypanosome agents, which possess better activities than existing drugs. The activity-based probes generated from this study could also serve as valuable tools for parasite-based proteome profiling studies, as well as bioimaging agents for studies of cellular uptake and distribution of these drug candidates. Our studies therefore provide a good starting point for further development of these azanitrile-containing compounds as potential anti-parasitic agents. Copyright
Azadipeptide nitriles: Highly potent and proteolytically stable inhibitors of papain-like cysteine proteases
Loeser, Reik,Frizler, Maxim,Schilling, Klaus,Guetschow, Michael
supporting information; experimental part, p. 4331 - 4334 (2009/02/08)
(Chemical Presented) Nitrogen instead of carbon: Azadipeptide nitriles resulting from CH/N exchange in the P1 position (see picture) are hitherto unknown. To access these compounds by conversion of amino acid-derived hydrazides with cyanogen bromide both nitrogen atoms of the hydrazide must be substituted. Despite a methylated P2-P1 peptide bond, the azadipeptide nitriles show a strong inhibitory activity against cysteine proteases, and a high stability towards chymotryptic hydrolysis.
1-peptidyl-2-haloacetyl hydrazines as active site directed inhibitors of papain and cathepsin B
Giordano,Calabretta,Gallina,Consalvi,Scandurra
, p. 1497 - 1516 (2007/10/02)
Fifteen 1-peptidyl-2-haloacetyl hydrazines, which can be considered halometanes of azapeptides containing Phe in P2 and α-aza-Ala or α-aza-Gly in P1, were synthesized and tested as models of cysteine-proteases inhibitors. By use of k
