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Sijbren Otto - One of the best experts on this subject based on the ideXlab platform.
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emergence of a new self replicator from a dynamic Combinatorial Library requires a specific pre existing replicator
Journal of the American Chemical Society, 2017Co-Authors: Yigit Altay, Meniz Tezcan, Sijbren OttoAbstract:Our knowledge regarding the early steps in the formation of evolvable life and what constitutes the minimal molecular basis of life remains far from complete. The recent emergence of systems chemistry reinvigorated the investigation of systems of self-replicating molecules to address these questions. Most of these studies focus on single replicators and the effects of replicators on the emergence of other replicators remains under-investigated. Here we show the cross-catalyzed emergence of a novel self-replicator from a dynamic Combinatorial Library made from a threonine containing peptide building block, which, by itself, only forms trimers and tetramers that do not replicate. Upon seeding of this Library with different replicators of different macrocycle size (hexamers and octamers), we observed the emergence of hexamer replicator consisting of six units of the threonine peptide only when it is seeded with an octamer replicator containing eight units of a serine building block. These results reveal for ...
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template triggered emergence of a self replicator from a dynamic Combinatorial Library
Journal of the American Chemical Society, 2015Co-Authors: Piotr Nowak, Mathieu Colombdelsuc, Sijbren OttoAbstract:Self-assembly of a specific member of a dynamic Combinatorial Library (DCL) may lead to self-replication of this molecule. However, if the concentration of the potential replicator in the DCL fails to exceed its critical aggregation concentration (CAC), then self-replication will not occur. We now show how addition of a template can raise the concentration of a Library member–template complex beyond its CAC, leading to the onset of self-replication. Once in existence, the replicator aggregates promote further replication also in the absence of the template that induced the initial emergence of the replicator.
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A "Dial-A-Receptor" Dynamic Combinatorial Library
Angewandte Chemie (International ed. in English), 2013Co-Authors: Saleh Hamieh, Piotr Nowak, Vittorio Saggiomo, Elio Mattia, R. Frederick Ludlow, Sijbren OttoAbstract:Making receptors to order: A small dynamic Combinatorial Library (DCL), formed from two dithiols in water, provides a continuous range of six receptors of different sizes. The majority of the 30 tested amines and ammonium ions amplified receptors from this Library, thus spanning the complete receptor-size range and showing that this DCL provides a generic platform for the development of receptors for this important class of compounds.
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templated amplification of a naphthalenediimide based receptor from a donor acceptor dynamic Combinatorial Library in water
Chemical Communications, 2009Co-Authors: Ho Yu Auyeung, Sijbren Otto, Dan G Pantos, Paolo Pengo, Jeremy K M SandersAbstract:We report a dynamic Combinatorial Library that, upon binding of an electronically-complementary guest, produces in high yield a tetrameric receptor with flat hydrophobic, electron-deficient surfaces and flexible, water-soluble disulfide-containing linkers; analysis of the dependence of Library composition on template concentration gives insight into the binding behaviours of the species involved.
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a catalyst for an acetal hydrolysis reaction from a dynamic Combinatorial Library
New Journal of Chemistry, 2005Co-Authors: Laurent Vial, Jeremy K M Sanders, Sijbren OttoAbstract:A transition-state analogue (TSA) for an acetal hydrolysis reaction was found to select and amplify a macrocycle from a dynamic Combinatorial Library (DCL) of disulfides in water. This host was able to accelerate the reaction by a factor of two; a similar value was progressively reached when the macrocycle was gradually produced in the course of the reaction.
Jeremy K M Sanders - One of the best experts on this subject based on the ideXlab platform.
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a remarkably flexible and selective receptor for ba2 amplified from a hydrazone dynamic Combinatorial Library
Chemical Communications, 2011Co-Authors: Jorg M Klein, Vittorio Saggiomo, Dan G Pantos, Lisa Reck, Mary Mcpartlin, Ulrich Luning, Jeremy K M SandersAbstract:A new [2+2] tetra-hydrazone macrocyclic receptor was significantly amplified in a dynamic Combinatorial Library upon templation with alkaline earth metal ions. After optimisation the product could be isolated in 95% yield and its interaction with ions was investigated by NMR and UV-Vis spectroscopy.
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amplifying different 2 catenanes in an aqueous donor acceptor dynamic Combinatorial Library
Journal of the American Chemical Society, 2009Co-Authors: Ho Yu Auyeung, Dan G Pantos, Jeremy K M SandersAbstract:Two donor−acceptor [2]catenanes have been synthesized and characterized from a single dynamic Combinatorial Library in water. One of these catenanes is different from earlier related interlocked molecules in that two donor units stack on each other in an unexpected order. Shifting the equilibrium by choosing the right conditions resulted in a significant increase in the yields of the individual catenanes.
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two phase dynamic Combinatorial discovery of a spermine transporter
Chemical Communications, 2009Co-Authors: Ruth Perezfernandez, Michael Pittelkow, Ana M Belenguer, Laura A Lane, Carol V Robinson, Jeremy K M SandersAbstract:The discovery, in a two-phase dynamic Combinatorial Library, of an unexpected linear receptor and transporter for spermine is described.
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templated amplification of a naphthalenediimide based receptor from a donor acceptor dynamic Combinatorial Library in water
Chemical Communications, 2009Co-Authors: Ho Yu Auyeung, Sijbren Otto, Dan G Pantos, Paolo Pengo, Jeremy K M SandersAbstract:We report a dynamic Combinatorial Library that, upon binding of an electronically-complementary guest, produces in high yield a tetrameric receptor with flat hydrophobic, electron-deficient surfaces and flexible, water-soluble disulfide-containing linkers; analysis of the dependence of Library composition on template concentration gives insight into the binding behaviours of the species involved.
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a catalyst for an acetal hydrolysis reaction from a dynamic Combinatorial Library
New Journal of Chemistry, 2005Co-Authors: Laurent Vial, Jeremy K M Sanders, Sijbren OttoAbstract:A transition-state analogue (TSA) for an acetal hydrolysis reaction was found to select and amplify a macrocycle from a dynamic Combinatorial Library (DCL) of disulfides in water. This host was able to accelerate the reaction by a factor of two; a similar value was progressively reached when the macrocycle was gradually produced in the course of the reaction.
Aleksandra Wyslouchcieszynska - One of the best experts on this subject based on the ideXlab platform.
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sequence specific ni ii dependent peptide bond hydrolysis for protein engineering Combinatorial Library determination of optimal sequences
Journal of the American Chemical Society, 2010Co-Authors: Artur Krezel, Edyta Kopera, Anna Maria Protas, Jaroslaw Poznanski, Aleksandra Wyslouchcieszynska, Wojciech BalAbstract:Previously we demonstrated for several examples that peptides having a general internal sequence R(N)-Yaa-Ser/Thr-Xaa-His-Zaa-R(C) (Yaa = Glu or Ala, Xaa = Ala or His, Zaa = Lys, R(N) and R(C) = any N- and C-terminal amino acid sequence) were hydrolyzed specifically at the Yaa-Ser/Thr peptide bond in the presence of Ni(II) ions at alkaline pH (Krezel, A., Mylonas, M., Kopera, E. and Bal, E. Acta Biochim. Polon. 2006, 53, 721-727 and references therein). Hereby we report the synthesis of a Combinatorial Library of CH(3)CO-Gly-Ala-(Ser/Thr)-Xaa-His-Zaa-Lys-Phe-Leu-NH(2) peptides, where Xaa residues included 17 common alpha-amino acids (except Asp, Glu, and Cys) and Zaa residues included 19 common alpha-amino acids (except Cys). The Ni(II)-dependent hydrolysis at 37 and 45 degrees C of batches of Combinatorial peptide mixtures randomized at Zaa was monitored by MALDI-TOF mass spectrometry. The correctness of Library-based predictions was confirmed by accurate measurements of hydrolysis rates of seven selected peptides using HPLC. The hydrolysis was strictly limited to the Ala-Ser/Thr bond in all Library and individual peptide experiments. The effects of individual residues on hydrolysis rates were quantified and correlated with physical properties of their side chains according to a model of independent contributions of Xaa and Zaa residues. The principal component analysis calculations demonstrated partial molar side chain volume and the free energy of amino acid vaporization for both Xaa and Zaa residues and the amine pK(a) for Zaa residues to be the most significant empirical parameters influencing the hydrolysis rate. Therefore, efficient hydrolysis required bulky and hydrophobic residues at both variable positions Xaa and Zaa, which contributed independently to the hydrolysis rate. This relationship between the peptide sequence and the hydrolysis rate provides a basis for further research, aimed at the elucidation of the reaction mechanism and biotechnological applications of Ni(II)-dependent peptide bond hydrolysis.
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sequence specific ni ii dependent peptide bond hydrolysis for protein engineering Combinatorial Library determination of optimal sequences
Journal of the American Chemical Society, 2010Co-Authors: Artur Krezel, Edyta Kopera, Anna Maria Protas, Jaroslaw Poznanski, Aleksandra WyslouchcieszynskaAbstract:Previously we demonstrated for several examples that peptides having a general internal sequence RN-Yaa-Ser/Thr-Xaa-His-Zaa-RC (Yaa = Glu or Ala, Xaa = Ala or His, Zaa = Lys, RN and RC = any N- and C-terminal amino acid sequence) were hydrolyzed specifically at the Yaa-Ser/Thr peptide bond in the presence of Ni(II) ions at alkaline pH (Krȩzel, A., Mylonas, M., Kopera, E., and Bal, E.Acta Biochim. Polon. 2006, 53, 721−727 and references therein). Hereby we report the synthesis of a Combinatorial Library of CH3CO-Gly-Ala-(Ser/Thr)-Xaa-His-Zaa-Lys-Phe-Leu-NH2 peptides, where Xaa residues included 17 common α-amino acids (except Asp, Glu, and Cys) and Zaa residues included 19 common α-amino acids (except Cys). The Ni(II)-dependent hydrolysis at 37 and 45 °C of batches of Combinatorial peptide mixtures randomized at Zaa was monitored by MALDI-TOF mass spectrometry. The correctness of Library-based predictions was confirmed by accurate measurements of hydrolysis rates of seven selected peptides using HPLC. The ...
Artur Krezel - One of the best experts on this subject based on the ideXlab platform.
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sequence specific ni ii dependent peptide bond hydrolysis for protein engineering Combinatorial Library determination of optimal sequences
Journal of the American Chemical Society, 2010Co-Authors: Artur Krezel, Edyta Kopera, Anna Maria Protas, Jaroslaw Poznanski, Aleksandra Wyslouchcieszynska, Wojciech BalAbstract:Previously we demonstrated for several examples that peptides having a general internal sequence R(N)-Yaa-Ser/Thr-Xaa-His-Zaa-R(C) (Yaa = Glu or Ala, Xaa = Ala or His, Zaa = Lys, R(N) and R(C) = any N- and C-terminal amino acid sequence) were hydrolyzed specifically at the Yaa-Ser/Thr peptide bond in the presence of Ni(II) ions at alkaline pH (Krezel, A., Mylonas, M., Kopera, E. and Bal, E. Acta Biochim. Polon. 2006, 53, 721-727 and references therein). Hereby we report the synthesis of a Combinatorial Library of CH(3)CO-Gly-Ala-(Ser/Thr)-Xaa-His-Zaa-Lys-Phe-Leu-NH(2) peptides, where Xaa residues included 17 common alpha-amino acids (except Asp, Glu, and Cys) and Zaa residues included 19 common alpha-amino acids (except Cys). The Ni(II)-dependent hydrolysis at 37 and 45 degrees C of batches of Combinatorial peptide mixtures randomized at Zaa was monitored by MALDI-TOF mass spectrometry. The correctness of Library-based predictions was confirmed by accurate measurements of hydrolysis rates of seven selected peptides using HPLC. The hydrolysis was strictly limited to the Ala-Ser/Thr bond in all Library and individual peptide experiments. The effects of individual residues on hydrolysis rates were quantified and correlated with physical properties of their side chains according to a model of independent contributions of Xaa and Zaa residues. The principal component analysis calculations demonstrated partial molar side chain volume and the free energy of amino acid vaporization for both Xaa and Zaa residues and the amine pK(a) for Zaa residues to be the most significant empirical parameters influencing the hydrolysis rate. Therefore, efficient hydrolysis required bulky and hydrophobic residues at both variable positions Xaa and Zaa, which contributed independently to the hydrolysis rate. This relationship between the peptide sequence and the hydrolysis rate provides a basis for further research, aimed at the elucidation of the reaction mechanism and biotechnological applications of Ni(II)-dependent peptide bond hydrolysis.
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sequence specific ni ii dependent peptide bond hydrolysis for protein engineering Combinatorial Library determination of optimal sequences
Journal of the American Chemical Society, 2010Co-Authors: Artur Krezel, Edyta Kopera, Anna Maria Protas, Jaroslaw Poznanski, Aleksandra WyslouchcieszynskaAbstract:Previously we demonstrated for several examples that peptides having a general internal sequence RN-Yaa-Ser/Thr-Xaa-His-Zaa-RC (Yaa = Glu or Ala, Xaa = Ala or His, Zaa = Lys, RN and RC = any N- and C-terminal amino acid sequence) were hydrolyzed specifically at the Yaa-Ser/Thr peptide bond in the presence of Ni(II) ions at alkaline pH (Krȩzel, A., Mylonas, M., Kopera, E., and Bal, E.Acta Biochim. Polon. 2006, 53, 721−727 and references therein). Hereby we report the synthesis of a Combinatorial Library of CH3CO-Gly-Ala-(Ser/Thr)-Xaa-His-Zaa-Lys-Phe-Leu-NH2 peptides, where Xaa residues included 17 common α-amino acids (except Asp, Glu, and Cys) and Zaa residues included 19 common α-amino acids (except Cys). The Ni(II)-dependent hydrolysis at 37 and 45 °C of batches of Combinatorial peptide mixtures randomized at Zaa was monitored by MALDI-TOF mass spectrometry. The correctness of Library-based predictions was confirmed by accurate measurements of hydrolysis rates of seven selected peptides using HPLC. The ...
Richard A Houghten - One of the best experts on this subject based on the ideXlab platform.
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discovery of a potent and selective α3β4 nicotinic acetylcholine receptor antagonist from an α conotoxin synthetic Combinatorial Library
Journal of Medicinal Chemistry, 2014Co-Authors: Yipin Chang, Richard A Houghten, Jayati Banerjee, Cheryl Dowell, Reena Gyanda, Lawrence Toll, Michael J Mcintosh, Christopher J ArmishawAbstract:α-Conotoxins are disulfide-rich peptide neurotoxins that selectively inhibit neuronal nicotinic acetylcholine receptors (nAChRs). The α3β4 nAChR subtype has been identified as a novel target for managing nicotine addiction. Using a mixture-based positional-scanning synthetic Combinatorial Library (PS-SCL) with the α4/4-conotoxin BuIA framework, we discovered a highly potent and selective α3β4 nAChR antagonist. The initial PS-SCL consisted of a total of 113 379 904 sequences that were screened for α3β4 nAChR inhibition, which facilitated the design and synthesis of a second generation Library of 64 individual α-conotoxin derivatives. Eleven analogues were identified as α3β4 nAChR antagonists, with TP-2212-59 exhibiting the most potent antagonistic activity and selectivity over the α3β2 and α4β2 nAChR subtypes. Final electrophysiological characterization demonstrated that TP-2212-59 inhibited acetylcholine evoked currents in α3β4 nAChRs heterogeneously expressed in Xenopus laevis oocytes with a calculated I...
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identification of inhibitors of prohormone convertases 1 and 2 using a peptide Combinatorial Library
Journal of Biological Chemistry, 1998Co-Authors: Ekaterina Apletalina, Richard A Houghten, Jon R Appel, Nazarius S Lamango, Iris LindbergAbstract:Abstract A positional scanning synthetic peptide Combinatorial Library containing approximately 52 million hexapeptides was used to identify potential inhibitory peptides for recombinant mouse prohormone convertase 1 (PC1) and PC2 and to provide information on the specificity of these enzymes. The Library surveys revealed that a P6 Leu, a P4 Arg, a P2 Lys, and a P1 Arg were most inhibitory against PC1, and a P6 Ile and a P4 Arg were most inhibitory against PC2. Using information derived from the Library surveys, hexapeptide sets were synthesized and screened for inhibition of PC1 and PC2. The data obtained revealed the preference of both enzymes for a P3 Val. At P5, many substitutions were well tolerated. PC1 and PC2 proved to differ mainly in the selectivity of their S6 subsites. In PC1, this subsite displayed a strong preference toward occupation by Leu; theK i value for peptide Ac-Leu-Leu-Arg-Val-Lys-Arg-NH2 was 28 times lower than that for peptide Ac-Ile-Ile-Arg-Val-Lys-Arg-NH2. In contrast, PC2 discriminated little between Leu and Ile at P6, as evidenced by the small (1.5-fold) difference in K i values for these two peptides. Several hexapeptides synthesized as a result of the screen were found to represent potent inhibitors of PC2 (withK i values in the submicromolar range) and, particularly, of PC1 (with K i values in the low nanomolar range). The most potent inhibitor, Ac-Leu-Leu-Arg-Val-Lys-Arg-NH2, proved to be the same peptide for both enzymes and inhibited PC1 and PC2 in a competitive, fast-binding manner with K i values of 3.2 and 360 nm, respectively. The four most potent peptide inhibitors of PC1 and PC2 were also tested against soluble human furin and found to exhibit a different rank order of inhibition; for example, Ac-Leu-Leu-Arg-Val-Lys-Arg-NH2 was 440-fold less potent against furin than against PC1, with a K i of 1400 nm.
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selective ligands for the μ δ and κ opioid receptors identified from a single mixture based tetrapeptide positional scanning Combinatorial Library
Journal of Biological Chemistry, 1998Co-Authors: Colette T Dooley, Jean M Bidlack, Richard A HoughtenAbstract:Abstract A Combinatorial Library of 6,250,000 tetrapeptides in the mixture based positional scanning format was screened in binding assays for the three opioid receptors, μ, δ, and κ. Three different binding profiles were found. Individual peptides were synthesized representing all possible combinations of the active amino acids identified from the screening data. New, highly active peptides selective for each of the three receptors were chosen. This study demonstrates the power of mixture-based Combinatorial libraries to identify distinctly different ligands for closely related receptors.
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novel antimicrobial compounds identified using synthetic Combinatorial Library technology
Trends in Biotechnology, 1996Co-Authors: Sylvie E Blondelle, Richard A HoughtenAbstract:The recent emergence of Combinatorial chemistry has greatly advanced the development of biologically active lead compounds. It is anticipated that Combinatorial Library technology will add great value to the fight against drug-resistant bacterial strains, which pose increasingly serious health hazards. Owing to the need to use complex cell-based assays and, in turn, to screen free compounds in solution, the potential use of Combinatorial libraries in the field of infectious diseases has not yet been fully explored. Despite these limitations, a number of new antimicrobial and/or antifungal compounds have been successfully identified from pools of millions of other compounds.
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an all d amino acid opioid peptide with central analgesic activity from a Combinatorial Library
Science, 1994Co-Authors: Colette T Dooley, Gavril W Pasternak, Peter W. Schiller, Brian C. Wilkes, N N Chung, Jean M Bidlack, Richard A HoughtenAbstract:A synthetic Combinatorial Library containing 52,128,400 D-amino acid hexapeptides was used to identify a ligand for the mu opioid receptor. The peptide, Ac-rfwink-NH2, bears no resemblance to any known opioid peptide. Simulations using molecular dynamics, however, showed that three amino acid moieties have the same spatial orientation as the corresponding pharmacophoric groups of the opioid peptide PLO17. Ac-rfwink-NH2 was shown to be a potent agonist at the mu receptor and induced long-lasting analgesia in mice. Analgesia produced by intraperitoneally administered Ac-rfwink-NH2 was blocked by intracerebroventricular administration of naloxone, demonstrating that this peptide may cross the blood-brain barrier.