Peptidomimetics via modifications of amino acids and peptide bonds

Avan, İlker; Hall, C. Dennis; Katritzky, Alan R.

doi:10.1039/c3cs60384a

Cited by 243 publications

(191 citation statements)

References 255 publications

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“…In future, chemical synthesis followed by in vitro and in vivo studies are required to establish the significance of this discovery. New technological developments in the field of peptidomics (Menschaert et al 2010;Mason 2010), peptidomimetics (Hruby and Cai 2013;Avan et al 2014) and drug design holds promise in modifying a primary peptide into a powerful inhibitor and subsequently to a peptide based drug.…”

Section: Resultsmentioning

confidence: 99%

In silico study of peptide inhibitors against BACE 1

et al. 2015

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Peptides are increasingly used as inhibitors of various disease specific targets. Several naturally occurring and synthetically developed peptides are undergoing clinical trials. Our work explores the possibility of reusing the non-expressing DNA sequences to predict potential drugtarget specific peptides. Recently, we experimentally demonstrated the artificial synthesis of novel proteins from non-coding regions of Escherichia coli genome. In this study, a library of synthetic peptides (Synpeps) was constructed from 2500 intergenic E. coli sequences and screened against Beta-secretase 1 protein, a known drug target for Alzheimer's disease (AD). Secondary and tertiary protein structure predictions followed by proteinprotein docking studies were performed to identify the most promising enzyme inhibitors. Interacting residues and favorable binding poses of lead peptide inhibitors were studied. Though initial results are encouraging, experimental validation is required in future to develop efficient target specific inhibitors against AD.

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Section: Resultsmentioning

confidence: 99%

In silico study of peptide inhibitors against BACE 1

et al. 2015

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“…These isosteres of natural dipeptides are proving valuable for producing mechanism based enzyme inhibitors and proteolytically stable peptides, both of which hold great promise as therapeutic agents [149].…”

Section: Peptidomimeticsmentioning

confidence: 99%

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

Kitson¹

2017

J Diagn Imaging Ther

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Molecular Metaphors is the application of squaryl building blocks towards creative functional group chemistry to produce lead compounds and imaging agents. This strategy is applied to rational drug design and to various imaging agents that would normally contain conventional functional group chemistry. These, include carboxylic acids, α-amino acids, peptide bonds and phosphonates. Moreover, the squaryl metaphor is a precursor to complex organic molecules involving functional group interchange (FGI) and rearrangements. This article discusses the application of these metaphors in the area of neurochemistry, especially NMDA receptors. An important area of drug design is the inhibition of angiotensin II enzyme by the use of losartan. This commercial drug contains a tetrazole moiety that can be modified using the squaryl group to give a semisquarate derivative. These concepts can extend to the semisquarate of ibuprofen. Moreover, a discussion on peptidomimetics regarding the substitution of the peptide bond for squaramide allows for a change in the biological properties due to modification at the peptide bond. Furthermore, the topic on how squaryl metaphors can be exploited primarily by the central 1,3-hydroxyamide sequence to the generation of a novel class of HIV protease inhibitors. Also, squaryl metaphors can be used to develop potential inhibitors of glutathione and novel anti-migraine drugs. The discussion continues on the design of anticancer drugs: in particular, a novel class of metalloproteases, including phosphonates for semisquaramides, leading to squaryl nucleosides. This review concludes with the application of squaryl metaphors in the design of positron emission tomography (PET) and magnetic resonance imaging (MRI) agents towards theranostics. describe the ability of individual functional chemical groups to mimic other moieties [2,3]. KeywordsErlenmeyer rationalised these concepts and categorised isosteres into atoms, ions and molecules based on the valence level of electrons [4]. A further understanding by Friedman led to the term bioisosterism to include all atoms and molecules that fit the broadest definition of isosteres [5]. This approach was independent of whether the drug was an agonist or an antagonist towards biological activity.Moreover, Thornber applied the term bioisosterism to include subunits, groups or molecules that possess physicochemical properties of similar biological effects [6]. Finally, in 1991 Burger widened the definition of bioisosteres to include compounds or groups that possess similar molecular shapes and volumes independent of agonists or antagonists [7]. REVIEW ARTICLE Squaryl KitsonThese bioisosteres would require approximately the same distribution of electrons and give a high probability of generating comparable physical properties such as hydrophobicity [8]. Currently, bioisosterism is one of the most useful tools to the medicinal chemist in rational drug design and in particular regarding the carboxylic acid bioisosteres [9]. The carboxylic acid functional ...

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“…The suspension was hydrogenated at rt and atmospheric pressure for 2 h. After filtration of the catalyst, the solvent was evaporated and the crude mixture was purified by column chromatography using EtOAc-hexane (11). To a solution of N-Pmp-2-oxoazetidine 7 (0.242 g, 0.55 mmol) in MeOH (100 mL), 10 wt% Pd/C was added (0.058 g, 0.06 mmol), and the suspension was hydrogenated at rt and atmospheric pressure for 6 h. After filtration of the catalyst, the solvent was evaporated and the crude mixture was purified by flash chromatography using MeOH-CH 2 After microwave heating at 120°C for 1 h, the solvent was evaporated to dryness and the residue was dissolved in EtOAc and washed with H 2 O and brine. The organic layer was dried over Na 2 SO 4 and evaporated to dryness.…”

Section: General Experimental Detailsmentioning

confidence: 99%

“…The organic layer was dried over Na 2 SO 4 and evaporated to dryness. The crude mixture was purified by chromatography on silica gel using MeOH-CH 2 (0.002 g, 0.01 mmol) and Boc 2 O (0.028 g, 0.13 mmol). After stirring at rt for 4 h, the solvent was removed under vacuum and the residue was dissolved in MeOH (3 mL).…”

Section: General Experimental Detailsmentioning

confidence: 99%