Combinatorial and Rational Strategies To Develop Nonpeptidic Î±4Î²7-Integrin Antagonists from Cyclic Peptides

Gottschling, Dirk; Boer, J. S. A. M. de; Schuster, Anja; Holzmann, Bernhard; Kessler, Horst

doi:10.1002/1521-3773(20020816)41:16<3007::aid-anie3007>3.0.co;2-3

Cited by 21 publications

(3 citation statements)

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“…Cross‐links (often called “bridges” or “staples”) include natural disulfides, lactones and lactams, as well as azo bonds between aromatic residues, double and triple bonds installed by ring‐closing olefin and alkyne metatheses, triazoles assembled by metal‐catalyzed alkyne–azide cycloadditions, urea, and a variety of thioethers in which various linchpins tie together two or more disulfide bonds . These strategies have provided clinical candidates with favorable activity and stability, and demonstrate the need for synthetic methods to enhance macrocycle diversity with control over geometry, charge and functional groups to probe structure–activity relationships (SAR) and improve biological activity.…”

Section: Methodsmentioning

confidence: 99%

Diversity‐Oriented Synthesis of Cyclic Azapeptides by A³‐Macrocyclization Provides High‐Affinity CD36‐Modulating Peptidomimetics

et al. 2017

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Macrocyclization has enabled the use of peptides in drug discovery creating a need for methods to synthesize diverse peptide macrocycles. Azapeptides have advanced to clinically used drugs, however, few cyclic azapeptides have been studied. A multiple component "A -macrocyclization" strategy is described for the preparation of diverse cyclic azapeptides and is demonstrated by the synthesis of 15 growth hormone releasing hormone-6 (GHRP-6) analogs. Certain cyclic aza-GHRP-6 analogs exhibited unprecedented affinity for the CD36 receptor, and capacity to modulate Toll-like receptor agonist-induced overproduction of nitric oxide, and reduce pro-inflammatory cytokine and chemokine production in macrophages.

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Section: Methodsmentioning

confidence: 99%

Diversity‐Oriented Synthesis of Cyclic Azapeptides by A³‐Macrocyclization Provides High‐Affinity CD36‐Modulating Peptidomimetics

et al. 2017

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“…It prevents tumor-induced angiogenesis and is currently in phase II clinical trials for the treatment of tumor metastasis of patients with renal or colon cancer. In principle, the conformation of the active constrained peptide can be used as structural input for depeptidization in hopes of discovering a nonpeptidic compound that retains activity [121].…”

Section: Lead Optimizationmentioning

confidence: 99%

Protein NMR in biomedical research

Jahnke

Widmer

2004

CMLS, Cell. Mol. Life Sci.

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Nuclear magnetic resonance (NMR) spectroscopy is a versatile biophysical technique with wide applicability in drug discovery research, particularly for the detection and characterization of molecular interactions. This review highlights in a comprehensive manner the aspects of biomolecular NMR which are most beneficial for pharmaceutical research and presents them as contributions to the different stages of a drug discovery program: target selection, assay development, lead generation and lead optimization. Emphasis is put on the concept of the particular NMR application, rather than on technical details, and on recent examples. Finally, an appendix of frequently asked questions is given.

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“…Although properties of macrocyclic peptides (so-called beyond Rule of 5; bRo5) lie outside the range of small molecule physical properties expected for “drug-likeness”, − they have gained substantial interest in pharmaceutical development. ,− Ease of synthesis, large-scale library exploration, diversity, , and rapid screening capabilities (e.g., phage and mRNA display) have all been contributing factors to the increased pursuit of macrocyclic peptides as drug candidates. Increased adoption of peptides as a therapeutic modality in recent years is evidenced by steadily increasing numbers of publications, as well as several cyclic peptides entering clinical trials …”

Section: Introductionmentioning

confidence: 99%

Conformational Strain of Macrocyclic Peptides in Ligand–Receptor Complexes Based on Advanced Refinement of Bound-State Conformers

et al. 2021

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Macrocyclic peptides are an important modality in drug discovery, but molecular design is limited due to the complexity of their conformational landscape. To better understand conformational propensities, global strain energies were estimated for 156 protein-macrocyclic peptide cocrystal structures. Unexpectedly large strain energies were observed when the bound-state conformations were modeled with positional restraints. Instead, low-energy conformer ensembles were generated using xGen that fit experimental X-ray electron density maps and gave reasonable strain energy estimates. The ensembles featured significant conformational adjustments while still fitting the electron density as well or better than the original coordinates. Strain estimates suggest the interaction energy in protein−ligand complexes can offset a greater amount of strain for macrocyclic peptides than for small molecules and non-peptidic macrocycles. Across all molecular classes, the approximate upper bound on global strain energies had the same relationship with molecular size, and bound-state ensembles from xGen yielded favorable binding energy estimates.

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Combinatorial and Rational Strategies To Develop Nonpeptidic Î±4Î²7-Integrin Antagonists from Cyclic Peptides

Cited by 21 publications

References 1 publication

Diversity‐Oriented Synthesis of Cyclic Azapeptides by A³‐Macrocyclization Provides High‐Affinity CD36‐Modulating Peptidomimetics

Diversity‐Oriented Synthesis of Cyclic Azapeptides by A³‐Macrocyclization Provides High‐Affinity CD36‐Modulating Peptidomimetics

Protein NMR in biomedical research

Conformational Strain of Macrocyclic Peptides in Ligand–Receptor Complexes Based on Advanced Refinement of Bound-State Conformers

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Combinatorial and Rational Strategies To Develop Nonpeptidic Î±4Î²7-Integrin Antagonists from Cyclic Peptides

Cited by 21 publications

References 1 publication

Diversity‐Oriented Synthesis of Cyclic Azapeptides by A3‐Macrocyclization Provides High‐Affinity CD36‐Modulating Peptidomimetics

Diversity‐Oriented Synthesis of Cyclic Azapeptides by A3‐Macrocyclization Provides High‐Affinity CD36‐Modulating Peptidomimetics

Protein NMR in biomedical research

Conformational Strain of Macrocyclic Peptides in Ligand–Receptor Complexes Based on Advanced Refinement of Bound-State Conformers

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Product

Resources

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Diversity‐Oriented Synthesis of Cyclic Azapeptides by A³‐Macrocyclization Provides High‐Affinity CD36‐Modulating Peptidomimetics

Diversity‐Oriented Synthesis of Cyclic Azapeptides by A³‐Macrocyclization Provides High‐Affinity CD36‐Modulating Peptidomimetics