- Michael Acceptor-Based Peptidomimetic Inhibitor of Main Protease from Porcine Epidemic Diarrhea Virus
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Porcine epidemic diarrhea virus (PEDV) causes high mortality in pigs. PEDV main protease (Mpro) plays an essential role in viral replication. We solved the structure of PEDV Mpro complexed with peptidomimetic inhibitor N3 carrying a Michael acceptor warhead, revealing atomic level interactions. We further designed a series of 17 inhibitors with altered side groups. Inhibitors M2 and M17 demonstrated enhanced specificity against PEDV Mpro. These compounds have potential as future therapeutics to combat PEDV infection.
- Wang, Fenghua,Chen, Cheng,Yang, Kailin,Xu, Yang,Liu, Xiaomei,Gao, Fan,Liu, He,Chen, Xia,Zhao, Qi,Liu, Xiang,Cai, Yan,Yang, Haitao
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p. 3212 - 3216
(2017/04/21)
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- Small-molecule inhibitor against MERS-CoV main protease, and preparation method and application thereof
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The invention provides a small-molecule inhibitor against MERS-CoV main protease. The small-molecule inhibitor is designed on the basis of the crystal structure of main protease of the novel coronavirus MERS-CoV. The invention also provides a synthetic method for the small-molecule inhibitor and application of the small-molecule inhibitor in preparation of drugs used for preventing and treating MERS-CoV infections. The small-molecule inhibitor against MERS-CoV main protease can substantially inhibit the activity of main protease of the MERS coronavirus, has good inhibitory activity to main protease of coronaviruses like SARS and MHV, and presents good application prospects in preparation of drugs used for preventing or treating coronavirus infections.
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- Ethyl 2-(tert-butoxycarbonyloxyimino)-2-cyanoacetate (Boc-Oxyma) as coupling reagent for racemization-free esterification, thioesterification, amidation and peptide synthesis
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Here we report the synthesis and utility of ethyl 2-(tert- butoxycarbonyloxyimino)-2-cyanoacetate (Boc-Oxyma) as an efficient coupling reagent for racemization-free esterification, thioesterification, amidation reactions and peptide synthesis that uses equimolar amounts of acids and alcohols, thiols, amines or amino acids, respectively. Its application to solid phase as well as solution phase peptide synthesis is also demonstrated and a mechanistic investigation is discussed. Boc-Oxyma is similar to the well known coupling agent COMU {1-[1-cyano-2-ethoxy-2-oxoethylideneaminooxy)- dimethylaminomorpholino] uronium hexafluorophosphate} in terms of its high reactivity and mechanism of action. However, it is not only much easier to prepare, but also to recover and reuse, thereby generating far less chemical waste.
- Thalluri, Kishore,Nadimpally, Krishna Chaitanya,Chakravarty, Maharishi Parasar,Paul, Ashim,Mandal, Bhubaneswar
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supporting information
p. 448 - 462
(2013/05/09)
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- Synthesis of a novel series of L-isoserine derivatives as aminopeptidase N inhibitors
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A series of novel L-isoserine derivatives were synthesised and evaluated for their ability to inhibit aminopeptidase N (APN)/CD13. In our preliminary biological results, some of these compounds possessed a potent inhibitory activity against the APN. Within this series, compound 14b not only showed similar enzyme inhibition (IC50 of 12.2μM) compared with the positive control bestatin (half maximal inhibitory concentration (IC 50) of 7.3μM), but also had a potent antiproliferative activity against human cancer cell lines cells.
- Yang, Kanghui,Fen, Jinghong,Fang, Hao,Zhang, Lei,Gong, Jianzhi,Xu, Wenfang
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p. 302 - 310
(2012/07/02)
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- Design, synthesis and biological evaluation of potent azadipeptide nitrile inhibitors and activity-based probes as promising anti-Trypanosoma brucei agents
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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
- Yang, Peng-Yu,Wang, Min,Li, Lin,Wu, Hao,He, Cynthia Y.,Yao, Shao Q.
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supporting information; experimental part
p. 6528 - 6541
(2012/07/13)
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- A metal-free oxidative esterification of the benzyl C-H bond
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An efficient metal-free oxidative esterification of benzyl C-H bonds was developed. Using tetrabutylammonium iodide as catalyst and tert-butyl hydroperoxide as co-oxidant, benzylic substrates could react smoothly with various carboxylic acids to give the esters with good to excellent yields. The method was also suitable for the O-protection of N-Boc amino acids. The reaction mechanism was primarily investigated and a radical process was proposed. Copyright
- Feng, Jie,Liang, Shuai,Chen, Shan-Yong,Zhang, Ji,Fu, Song-Sen,Yu, Xiao-Qi
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experimental part
p. 1287 - 1292
(2012/06/15)
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- Catalyst and solvent-free amidation of inactive esters of N-protected amino acids
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A catalyst free procedure for the preparation of amides from inactive esters of N-protected amino acids and various amines is demonstrated under mild reaction conditions. Our effort to recover excess amine and generated alcohol is an approach towards environment friendly and cost effective synthesis under easy operational conditions.
- Nadimpally, Krishna Chaitanya,Thalluri, Kishore,Palakurthy, Nani Babu,Saha, Abhijit,Mandal, Bhubaneswar
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supporting information; experimental part
p. 2579 - 2582
(2011/06/21)
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- From peptides to their alternating ester-urea analogues: Synthesis and influence of hydrogen bonding motif and stereochemistry on aggregation
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(Chemical Equation Presented) Peptide-mimicking scaffolds with an incorporated ester-urea motif, replacing two adjacent amide residues, were synthesized and their aggregation behavior was studied in dependence of hydrogen bonding sites as well as backbone stereochemistry. Two oligomer series containing either 50% or 100% ester-urea units and either all-(L) or (D)-alt-(L) backbone configuration were prepared via ester and amide couplings, using a divergent/convergent exponential growth strategy. Their aggregation behavior in organic solution was investigated by means of concentration-dependent NMR spectroscopy and compared to the parent peptide series. Interestingly, the naturally occurring peptide scaffold exhibits the largest tendency to associate in combination with the strongest difference in aggregation behavior between all-(L) and (D)-alt-(L) backbone stereochemistry. With increasing incorporation of the ester-urea motif the aggregation strength decreases and become much less dependent on the backbone configuration. The obtained structure-aggregation relationships reveal the importance of the commensurability and multivalency of hydrogen bonding sites as well as conformational restriction for peptide association and should hence aid the design of peptide mimics, such as β -sheet breakers or gelators. 2009 American Chemical Society.
- Hartwig, Sebastian,Schwarz, Jutta,Hecht, Stefan
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supporting information; experimental part
p. 772 - 782
(2010/07/05)
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- PEPTIDIC COMPOUNDS
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The present invention provides a compound of formula (I), (II), (III) and (IV) as defined herein and pharmaceutically acceptable derivatives thereof. The present invention further provides use of the compounds of the present invention in the treatment of bacterial infection and in the treatment of HIV infection. Also provided are pharmaceutical compositions comprising the compounds of the present invention.
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Page/Page column 27; 31
(2008/06/13)
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- Effect of PNA backbone modifications on cyanine dye binding to PNA-DNA duplexes investigated by optical spectroscopy and molecular dynamics simulations
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Optical spectroscopy and molecular dynamics simulations have been used to study the interaction between a cationic cyanine dye and peptide nucleic acid (PNA)-DNA duplexes. This recognition event is important because it leads to a visible color change, signaling successful hybridization of PNA with a complementary DNA strand. We previously proposed that the dye recognized the minor groove of the duplex, using it as a template for the assembly of a helical aggregate. Consistent with this, we now report that addition of isobutyl groups to the PNA backbone hinders aggregation of the dye when the substituents project into the minor groove but have a weaker effect if directed out of the groove. UV-Visible and circular dichroic spectroscopy were used to compare aggregation on the different PNA-DNA duplexes, while molecular dynamics simulations were used to confirm that the substituents block the minor groove to varying degrees, depending on the configuration of the starting amino acid. In addition to a simple steric blockage effect of the substituent, the simulations suggest that directing the isobutyl group into the minor groove causes the groove to narrow and the duplex to become more rigid, structural perturbations that are relevant to the growing interest in backbone-modified PNA for applications in the biological and materials sciences.
- Dilek, Isil,Madrid, Marcela,Singh, Rojendra,Urrea, Christian P.,Armitage, Bruce A.
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p. 3339 - 3345
(2007/10/03)
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- Restricted conformation analogues of an anthelmintic cyclodepsipeptide
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Six analogues of the anthelmintic cyclodepsipeptide PF1022A were prepared, each containing a small ring fused to the macrocycle to restrict the number of conformations the larger ring can adopt. It was anticipated that such conformational changes could lead to enhanced biological activity and selectivity. The analogues form two series of three members each. In one series, a carbon-based molecular bridge joins the methyl of a leucine residue with the methyl of its closest lactic acid residue to form five-, six-, and seven-membered lactam rings. In the second series, a leucine residue is replaced with five-, six-, and seven-membered nitrogen heterocycles. Decreasing the size of the small ring in the lactam series increasingly distorts the macrocycle and consistently decreases activity relative to PF1022A. In the leucine series, a similar trend is observed. Molecular modeling of PF1022A along with the analogues described herein suggests that the ability to exist in a highly symmetrical conformational state is a necessary condition for biological activity.
- Dutton, Fred E.,Lee, Byung H.,Johnson, Sandra S.,Coscarelli, Eileen M.,Lee, Pil H.
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p. 2057 - 2073
(2007/10/03)
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- Application of a unique automated synthesis system for solution-phase peptide synthesis
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An automated synthesis system, which is suitable for repetitive syntheses using similar reaction procedures, was used to synthesize systematically a library of all possible dipeptides (25) and tripeptides (125) from 5 protected amino acids. The apparatus has also been applied to the automated synthesis of 10 fragment tripeptide derivatives that are constituents of the hormone PACAP-27. The measured molecular optical rotation values of the library of 125 tripeptides were found to correlate well with calculated values obtained by summation of the molecular optical rotation values for the constituent amino acids.
- Sugawara,Kobayashi,Okamoto,Kitada,Fujino
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p. 1272 - 1280
(2007/10/02)
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- Preparation and Properties of Nα-Di-tert-Butoxycarbonyl Amino Acids. Applicability in the Synthesis of Leu-Enkephalin
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The synthesis of Nα-di-tert-butoxycarbonyl amino acids starting from the corresponding mono-derivatives via a three-step route is reported.The latter were converted into a suitable ester and then exhaustively t-butoxycarbonylated, after which t
- Gunnarsson, Kerstin,Ragnarsson, Ulf
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p. 944 - 951
(2007/10/02)
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