Nonspecific protease-catalyzed hydrolysis/synthesis of a mixture of peptides: Product diversity and ligand amplification by a molecular trap

Swann, Patrick G.; Casanova, Rose A.; Desai, Archana; Frauenhoff, Mary M.; Urbancic, Minka; Słomczyńska, Urszula; Hopfinger, A. J.; Breton, Guy C. Le; Venton, D. L.

doi:10.1002/(sici)1097-0282(1996)40:6<617::aid-bip3>3.0.co;2-z

Cited by 106 publications

(61 citation statements)

References 17 publications

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“…Addition of dinaphtho -crown ether 6 led to the formation of [2]catenane 5 [22] . reversibly, with a view to amplifying the sequences that bound most strongly to fi brinogen [27] . In 1997, Miller et al .…”

Section: Early DCL Smentioning

confidence: 99%

History and Principles of Dynamic Combinatorial Chemistry

Beeren

Sanders

2010

Dynamic Combinatorial Chemistry

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Section: Early DCL Smentioning

confidence: 99%

History and Principles of Dynamic Combinatorial Chemistry

Beeren

Sanders

2010

Dynamic Combinatorial Chemistry

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“…Each of them has its own characteristics, advantages and drawbacks. For the construction of DCLs in the presence of a biological target imine, acylhydrazone formation [13,[22][23][24][25][26][27][28][29], disulfide exchange [30][31][32][33], transamidation [34], transthioesterification [35], enzyme-catalyzed aldol reaction [36,37], cross-metathesis [38,39] and boronate transesterification [40] have been reported. The C=N bond formation processes, by condensation of an amino group with carbonyl functionalities, are (besides disulfide exchange) the most important class of DCC reactions and have proven to be efficient when biological systems are targeted.…”

Section: Generation Of Diversity: DCC Reactions and Building Blocksmentioning

confidence: 99%

“…An early related case made use of a monoclonal antibody (against b-endorphin) as a molecular target capable of driving the reversible synthesis/hydrolysis of a peptide mixture towards the formation of the specific antibody binder [34] ( Fig. 16.2).…”

Section: Application Of DCC To Biological Systemsmentioning

confidence: 99%

Dynamic Combinatorial Diversity in Drug Discovery

Hochgürtel¹,

Lehn

2006

Methods and Principles in Medicinal Chemistry

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IntroductionCombinatorial chemistry evolved as a key technology for the rapid generation of large populations of structurally distinct molecules that can be screened efficiently en masse for desirable properties. This approach, in combination with highthroughput screening, evolved into a powerful technique capable of significantly accelerating the drug discovery process [1]. Initially developed to produce peptide libraries for screening against antibodies or receptors, combinatorial synthesis and the screening of combinatorial arrays became an integral part in lead generation and optimization in drug discovery [2][3][4][5]. Furthermore, combinatorial methodologies also demonstrated their potential in other areas, such as the development and discovery of catalysts, and material science [6,7].Modern combinatorial libraries are characterized by the generation of numerous different, but structurally related compounds that exist discretely as static entities, under similar conditions, in a systematic manner. Currently, there are several distinct methodologies for the generation of combinatorial libraries [8,9]. These combinatorial arrays can be produced in a parallel fashion, either as a library of individual compounds or as pooled mixtures. In applying a parallel format, the compounds are handled individually in separated compartments. This removes difficulties associated with compound mixtures; and it allows for every individual compound a straightforward evaluation of chemical integrity and structure-activity relationship after biological testing. The library size handled with this methodology is more limited than in a pooling strategy. Pooled mixture formation is straightforward and less time-consuming than the synthesis of individual compounds. More difficult is the analysis and screening of mixtures of components. By the split and mix technology, very large libraries can be formed progressively over multiple synthetic steps. Also, several technological advances in solid phase automated synthesis, analysis, robotics and miniaturization allow the rapid parallel synthesis and characterization of very large arrays of individual compounds. The substances generated are then subsequently evaluated for biological activity by high-throughput screening, applying fully automated systems towards a chosen target protein. 341Fragment-based Approaches in Drug Discovery. Edited

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“…Multiple examples have been reported over the years of using the biological targets as templates for formation of ligands from smaller building blocks. This formation is accomplished either by acceleration of a chemical reaction between the blocks (3)(4)(5)(6) or by binding of effective building block combinations by the template, thus shifting the equilibrium between multiple possible combinations to the preferred route (7). Dynamic combinatorial chemistry (DCC) has emerged recently as a coherent approach to self-organization of molecular libraries, thermodynamically driven by the target (8)(9)(10)(11)(12)(13).…”

mentioning

confidence: 99%

Target-induced formation of neuraminidase inhibitors from in vitro virtual combinatorial libraries

Hochgürtel¹,

Kroth²,

Piecha³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

139

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Neuraminidase, a key enzyme responsible for influenza virus propagation, has been used as a template for selective synthesis of small subsets of its own inhibitors from theoretically highly diverse dynamic combinatorial libraries. We show that the library building blocks, aldehydes and amines, form significant amounts of the library components resulting from their coupling by reductive amination only in the presence of the enzyme. The target amplifies the best hits at least 120-fold. The dynamic libraries synthesized and screened in such an in vitro virtual mode form the components that possess high inhibitory activity, as confirmed by enzyme assays with independently synthesized individual compounds.

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Nonspecific protease-catalyzed hydrolysis/synthesis of a mixture of peptides: Product diversity and ligand amplification by a molecular trap

Cited by 106 publications

References 17 publications

History and Principles of Dynamic Combinatorial Chemistry

History and Principles of Dynamic Combinatorial Chemistry

Dynamic Combinatorial Diversity in Drug Discovery

Target-induced formation of neuraminidase inhibitors from in vitro virtual combinatorial libraries

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