Phage-encoded bismuth bicycles enable instant access to targeted bioactive peptides

Communications Chemistry, Journal Year: 2024, Volume and Issue: 7(1)

Published: June 27, 2024

Abstract Genetically encoded libraries play a crucial role in discovering structurally rigid, high-affinity macrocyclic peptide ligands for therapeutic applications. Bicyclic peptides with metal centres like bismuth were recently developed as new type of constrained notable affinity, stability and membrane permeability. This study represents the genetic encoding peptide-bismuth peptide-arsenic bicycles phage display. We introduce tripotassium dicitrate (gastrodenol) water-soluble bismuth(III) reagent library modification situ bicyclic preparation, eliminating need organic co-solvents. Additionally, we explore arsenic(III) an alternative thiophilic element that is used analogously to our previously introduced core. The these elements instantaneous entirely biocompatible, offering advantage over conventional alkylation-based methods. In pilot display screening campaign aimed at identifying biotin-binding protein streptavidin, demonstrate enrichment dissociation constants two orders magnitude lower than those their linear counterparts, underscoring impact structural constraint on binding affinity.

Language: Английский

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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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Peptide–Bismuth Tricycles: Maximizing Stability by Constraint

Chemistry - A European Journal, Journal Year: 2025, Volume and Issue: 31(8)

Published: Jan. 13, 2025

Abstract Constrained peptides possess excellent properties for identifying lead compounds in drug discovery. While it has become increasingly straightforward to discover selective high‐affinity peptide ligands, especially through genetically encoded libraries, their stability and bioavailability remain significant challenges. By integrating macrocyclization chemistry with bismuth binding, we generated series of linear, cyclic, bicyclic, tricyclic identical sequences. Utilizing rigidify the structure allows a better comparison different constraint levels, reducing confounding effects interactions often seen hydrophobic stapling reagents. Our study facilitated identification peptide–bismuth tricycle that fully withstands cellular levels glutathione, acts as nanomolar protease inhibitor without being proteolytically digested by its target, is stable human plasma. Importantly, this multicyclic does not any non‐canonical amino acid modifications. Using oxime ligation, conjugated an analogue N‐terminus two nanobodies demonstrate potential applications targeted therapy.

Language: Английский

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Synthesis and stability studies of constrained peptide–antimony bicycles

Australian Journal of Chemistry, Journal Year: 2024, Volume and Issue: 77(9)

Published: Aug. 27, 2024

Peptide therapeutics play an increasingly important role in modern drug discovery. Improving the pharmacokinetic profile of bioactive peptides has been effectively achieved with chemical modifications, especially macrocyclisation reactions. Consequently, there is a great demand for highly constrained compounds such as bicyclic peptides. In our previous research, we introduced peptide–bismuth bicycles and peptide–arsenic new classes this work, extend peptide bicyclisation strategy towards antimony. Similar to arsenic bismuth, antimony(III) selectively binds three cysteine residues peptides, enabling situ formation stable bicycles. The reaction occurs instantaneously under biocompatible conditions at physiological pH. Antimony–peptide remain largely intact presence common metal chelator ethylenediaminetetraacetic acid (EDTA) main endogenous thiol competitor glutathione (GSH). Furthermore, when challenged bismuth(III) from water-soluble gastrodenol (bismuth tripotassium dicitrate), antimony–peptide convert into corresponding bismuth–peptide bicycle, highlighting superior thiophilicity bismuth over other pnictogens. Our study further expands toolbox multicyclisation group elements previously underexplored biology.

Language: Английский

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Non-Symmetric Cysteine Stapling in Native Peptides and Proteins

Chemical Communications, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 10, 2024

The bifunctional reagent 2-chloromethyl-6-cyanopyridine enables biocompatible, non-symmetric stapling of N-terminal and internal cysteines. Stapled peptides exhibit improved affinity, inhibition stability can be displayed on proteins.

Language: Английский

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Engineered Nanobodies Bind Bismuth, Indium and Gallium for Applications in Theranostics

Angewandte Chemie, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 31, 2024

Abstract Targeted theranostics heavily rely on metal isotopes conjugated to antibodies. Single‐domain antibodies, known as nanobodies, are much smaller in size without compromising specificity and affinity. The conventional way of conjugating metals nanobodies involves non‐specific modification amino acid residues with bifunctional chelating agents. We demonstrate that mutagenesis a single residue nanobody creates triple cysteine motif selectively binds bismuth which is, for example, used targeted alpha therapy. Two mutations create quadruple mutant specific gallium indium positron emission tomography single‐photon computed tomography, respectively. Labelling is quantitative within few minutes. maintain structural integrity stability over weeks, resist competition from endogenous binders like glutathione, retain functionality.

Language: Английский

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Engineered Nanobodies Bind Bismuth, Indium and Gallium for Applications in Theranostics

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 31, 2024

Targeted theranostics heavily rely on metal isotopes conjugated to antibodies. Single-domain antibodies, known as nanobodies, are much smaller in size without compromising specificity and affinity. The conventional way of conjugating metals nanobodies involves non-specific modification amino acid residues with bifunctional chelating agents. We demonstrate that mutagenesis a single residue nanobody creates triple cysteine motif selectively binds bismuth which is, for example, used targeted alpha therapy. Two mutations create quadruple mutant specific gallium indium positron emission tomography single-photon computed tomography, respectively. Labelling is quantitative within few minutes. maintain structural integrity stability over weeks, resist competition from endogenous binders like glutathione, retain functionality.

Language: Английский

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De novo discovery of bicycles

Nature Chemical Biology, Journal Year: 2024, Volume and Issue: 21(1), P. 29 - 31

Published: Dec. 24, 2024

Language: Английский

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