1,2,3‐Triazole as a Peptide Surrogate in the Rapid Synthesis of HIV‐1 Protease Inhibitors

Brik, Ashraf; Alexandratos, Jerry; Lin, Ying‐Chuan; Elder, John H.; Olson, Arthur J.; Wlodawer, Alexander; Goodsell, David S.; Wong, Chi‐Huey

doi:10.1002/cbic.200500101

Cited by 278 publications

(158 citation statements)

References 12 publications

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“…The next series of molecules probed whether the hydrogen bonding acceptor and donor nature of the C-7 carboxylate/amide could be mimicked with triazoles, 32,33 guanidines, or sulfonate. The results of the kinetic studies imply that guanidine groups (as in 6 and 7) are inadequate mimics in this context.…”

Section: Discussionmentioning

confidence: 99%

Exploring structural motifs necessary for substrate binding in the active site of Escherichia coli pantothenate kinase

Awuah¹,

Ma²,

Hoegl³

et al. 2014

Bioorganic & Medicinal Chemistry

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The coenzyme A (CoA) biosynthetic enzymes have been used to produce various CoA analogues, including mechanistic probes of CoA-dependent enzymes such as those involved in fatty acid biosynthesis. These enzymes are also important for the activation of the pantothenamide class of antibacterial agents, and of a recently reported family of antibiotic resistance inhibitors. Herein we report a study on the selectivity of pantothenate kinase, the first and rate limiting step of CoA biosynthesis. A robust synthetic route was developed to allow rapid access to a small library of pantothenate analogs diversified at the β-alanine moiety, the carboxylate or the geminal dimethyl group. All derivatives were tested as substrates of Escherichia coli pantothenate kinase (EcPanK). Four derivatives, all N-aromatic pantothenamides, proved to be equivalent to the benchmark Npentylpantothenamide (N5-pan) as substrates of EcPanK, while two others, also with N-aromatic groups, were some of the best substrates reported for this enzyme. This collection of data provides insight for the future design of PanK substrates in the production of useful CoA analogues. Graphical abstractThe promiscuity of E. coli PanK has limits! We report the synthesis of pantothenate analogs diversified at the β-alanine moiety, the carboxylate or the geminal dimethyl group. Interestingly, some of these are among the best substrates reported for E. coli PanK.

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Section: Discussionmentioning

confidence: 99%

Exploring structural motifs necessary for substrate binding in the active site of Escherichia coli pantothenate kinase

Awuah¹,

Ma²,

Hoegl³

et al. 2014

Bioorganic & Medicinal Chemistry

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“…Similar approaches comparing the structures of FIV and drug-resistant HIV-1 PRs to that of WT HIV-1 PR have led to the development of additional PR-inhibiting compounds with broadened efficacy (8,9,19,29,41,42). Our approach in studying substrate and inhibitor specificities has been to exchange amino acid residues in and around the active site of FIV PR with structurally equivalent residues of HIV-1 PR.…”

mentioning

confidence: 99%

Generation of Infectious Feline Immunodeficiency Virus (FIV) Encoding FIV/Human Immunodeficiency Virus Chimeric Protease

Lin¹,

Torbett

Elder³

2010

J Virol

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Feline immunodeficiency virus (FIV) and human immunodeficiency virus type 1 (HIV-1) proteases (PRs)share only 23% amino acid identity and exhibit distinct specificities yet have very similar 3-dimensional structures. Chimeric PRs in which HIV residues were substituted in structurally equivalent positions in FIV PR were prepared in order to study the molecular basis of PR specificity. Previous in vitro analyses showed that such substitutions dramatically altered the inhibitor specificity of mutant PRs but changed the rate and specificity of Gag cleavage so that chimeric FIVs were not infectious. Chimeric PRs encoding combinations of the I37V, N55M, M56I, V59I, L97T, I98P, Q99V, and P100N mutations were cloned into FIV Gag-Pol, and those constructs that best approximated the temporal cleavage pattern generated by wild-type FIV PR, while maintaining HIV-like inhibitor specificity, were selected. Two mutations, M56I and L97T, were intolerant to change and caused inefficient cleavage at NC-p2. However, a mutant PR with six substitutions (I37V, N55M, V59I, I98P, Q99V, and P100N) was selected and placed in the context of full-length FIV-34TF10. This virus, termed YCL6, had low-level infectivity ex vivo, and after passage, progeny that exhibited a higher growth rate emerged. The residue at the position of one of the six mutations, I98P, further mutated on passage to either P98H or P98S. Both PRs were sensitive to the HIV-1 PR inhibitors lopinavir (LPV) and darunavir (DRV), as well as to the broad-based inhibitor TL-3, with 50% inhibitory concentrations (IC 50 ) of 30 to 40 nM, consistent with ex vivo results obtained using mutant FIVs. The chimeras offer an infectivity system with which to screen compounds for potential as broad-based PR inhibitors, define structural parameters that dictate specificity, and investigate pathways for drug resistance development.

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“…Reaction between methyl-2-aminobenzoate and phenyl isothiocyanate afforded the corresponding thiosemicarbazide derivatives (11) in moderate yield (Scheme (3)). The FTIR spectra of (11) display (C=S) stretching band at (1255cm -1) ) and (NH) stretching band at (3247cm -1 ) .Refluxing of compound (11) with ethylchloroacetate and anhydrous sodium acetate in absolute ethanol for six hours afforded 4-thiazolidenone (12). The structure of(12) was confirmed by the presence of (C=O amid ) stretching band at (1689cm On the other hand the reaction of methyl-2-aminobenzoate with hydrazine hydrate.…”

Section: Resultsmentioning

confidence: 99%

“…Recently it was found that 1,2,3-triazoles could be used as a peptide surrogates in the rapid synthesis of HIV-1 protease inhibitors [12] and as cis peptide bond surrogate in protein prosthesis [13].It was found that pyrazole and 4-thiazolidinone derivatives have additional industrial applications [14], [15].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Characterization of Some New 1,2,3-Triazole, Pyrazolin-5-one and thiazolidinone Derivatives

Hassan

2013

JNUS

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Five membered heterocyclics derivatives were synthesized in this work by three routes. The first route includes the synthesis of N-benzoic acid 1,2,3,-triazole derivatives (3),(4) by diazotation of methyl-2-amino benzoate and treating the resulted salt (1) with sodium azide and ethyl acetoacetate or acetyl acetone, respectively. In the second route, derivatives of pyrazole (8) pyrazolin-5-one (9), (10) were prepared by the reaction of the salt (1) with some active methylene compounds to give the corresponding hydrazones derivatives (5-7) which then they were treated with hydrazine hydrate. The third route afforded the synthesis of three derivatives (12), (15a), (15b) of thiazolidinone by two different methods. AII compounds were confirmed by their melting points, FTIR, U.V-vis spectra and 1 H-NMR spectra for some of them.

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1,2,3‐Triazole as a Peptide Surrogate in the Rapid Synthesis of HIV‐1 Protease Inhibitors

Cited by 278 publications

References 12 publications

Exploring structural motifs necessary for substrate binding in the active site of Escherichia coli pantothenate kinase

Exploring structural motifs necessary for substrate binding in the active site of Escherichia coli pantothenate kinase

Generation of Infectious Feline Immunodeficiency Virus (FIV) Encoding FIV/Human Immunodeficiency Virus Chimeric Protease

Synthesis and Characterization of Some New 1,2,3-Triazole, Pyrazolin-5-one and thiazolidinone Derivatives

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