Selection of Nucleotide-Encoded Mass Libraries of Macrocyclic Peptides for Inaccessible Drug Targets

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(21), P. 12213 - 12241

Published: Oct. 25, 2024

Technological advances and breakthrough developments in the pharmaceutical field are knocking at door of "undruggable" fortress with increasing insistence. Notably, 21st century has seen emergence macrocyclic compounds, among which cyclic peptides particular interest. This new class potential drug candidates occupies vast chemical space between classic small-molecule drugs larger protein-based therapeutics, such as antibodies. As research toward clinical targets that have long been considered inaccessible, well-suited to tackle these challenges a post-rule 5 landscape. Facilitating their discovery is an arsenal high-throughput screening methods exploit massive randomized libraries genetically encoded compounds. These techniques benefit from incorporation non-natural moieties, non- proteinogenic amino acids or stabilizing hydrocarbon staples. Exploiting features for strategic architectural design challenging protein–protein interactions, resisted efforts. Review summarizes basic principles recent main focuses on specific deployment targeting undruggable space. A focus placed development guidelines cyclization structural stabilization resulting success stories achieved against well-known inaccessible targets.

Language: Английский

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Strand-Swapped SH3 Domain Dimer with Superoxide Dismutase Activity

ACS Central Science, Journal Year: 2025, Volume and Issue: 11(1), P. 157 - 166

Published: Jan. 10, 2025

The design of metalloproteins allows us to better understand metal complexation in proteins and the resulting function. In this study, we incorporated a Cu2+-binding site into natural protein domain, 58 amino acid c-Crk-SH3, create miniaturized superoxide dismutase model, termed SO1. low complexity metalloprotein was characterized for structure function by circular dichroism UV spectroscopy as well EPR X-ray crystallography. miniprotein found be strand-swapped dimer with an unusual coupled binuclear Type 2-like copper center each protomer. SO1-Cu SOD-active activity only 1 order magnitude lower than that SOD enzymes 2 orders higher other low-complexity models similar size. This serendipitous provides new structural template future designs different ions functions.

Language: Английский

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A bioinformatics approach to the design of minimal biomimetic metal-binding peptides

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: March 10, 2025

Nature-inspired or biomimetic catalyst aims to reach the high catalytic performance and selectivity of natural enzymes while possessing chemical stability processability synthetic catalysts. A promising strategy for designing catalysts holds on mimicking structure enzyme active site. This can either entail complicated total synthesis a design peptide sequences, able self-assemble in presence metal ions, thus forming metallo-peptide complexes that mimic sites enzymes. Using bioinformatics approach, we designed minimal made up eight amino acids (H4pep) act as functional trinuclear Cu site laccase enzyme. Cu(II) binding H4pep results formation Cu²⁺(H4pep)₂ complex with β-sheet secondary structure, reduce O₂. Our study demonstrates viability potential using short peptides Teaser peptide, via bioinformatics, effectively mimics copper O₂ reduction. MAIN TEXT

Language: Английский

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Thermostable WW-Domain Scaffold to Design Functional β-Sheet Miniproteins

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(24), P. 16590 - 16600

Published: June 10, 2024

There has been a recent surge in the design of miniproteins for medicinal chemistry, biomaterial design, or synthetic biology. In particular, there is an interest peptide scaffolds that fold reliably, predictably, and with solid stability. this article, we present highly thermostable WW domain, three-stranded β-sheet motif, superior melting temperature about 90 °C to serve as core scaffold onto which receptor-like properties can be grafted. We have performed specific rounds sequence iteration on WW-domain consensus decipher positions affect structural and, thus, thermal identified sequence-structure relationship yields scaffold. High-resolution NMR spectroscopy was applied, enabled identification features at atomic scale contribute high thermostability. Finally, grafted binding motifs three groups─Group I, Group II/III, IV─and organophosphate metal obtained

Language: Английский

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Crystallography reveals metal‐triggered restructuring of β‐hairpins

Chemistry - A European Journal, Journal Year: 2024, Volume and Issue: 30(59)

Published: Aug. 17, 2024

Metal binding to β-sheets occurs in many metalloproteins and is also implicated the pathology of Alzheimer's disease. De novo designed metallo-β-sheets have been pursued as models mimics these proteins. However, no crystal structures canonical β-sheet metallopeptides yet obtained, stark contrast examples for ɑ-helical metallopeptides, leading a poor understanding their chemistry. To address this, we engineered tryptophan zippers, stable 12-residue peptides, bind Cu(II) ions obtained through single X-ray diffraction (SC-XRD). We find that metal triggers several unexpected supramolecular assemblies demonstrate range higher-order available metallo-β-sheets. Overall, findings underscore importance crystallography elucidating rich structural landscape metallo-β-sheet peptides.

Language: Английский

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Enhanced Biochemical Properties of Soybean Root Nodule Asparaginase through Plant Molecular Farming Compared to Bacterial Enzyme for Cancer Treatment

Rhizosphere, Journal Year: 2024, Volume and Issue: unknown, P. 100970 - 100970

Published: Oct. 1, 2024

Language: Английский

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