A5066584687- Chemical Synthesis and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Click Chemistry and Applications
- Biochemical and Structural Characterization
- Glycosylation and Glycoproteins Research
- Peptidase Inhibition and Analysis
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Protease and Inhibitor Mechanisms
- Blood Coagulation and Thrombosis Mechanisms
- Antimicrobial Peptides and Activities
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Advanced biosensing and bioanalysis techniques
- Advanced Biosensing Techniques and Applications
- RNA and protein synthesis mechanisms
- Bacteriophages and microbial interactions
- DNA Repair Mechanisms
- Biotin and Related Studies
- Advanced Proteomics Techniques and Applications
- DNA and Nucleic Acid Chemistry
- S100 Proteins and Annexins
- Microbial Natural Products and Biosynthesis
- Bacterial Genetics and Biotechnology
- Innovative Microfluidic and Catalytic Techniques Innovation
- Mast cells and histamine
École Polytechnique Fédérale de Lausanne
2016-2025
Robert Bosch (Germany)
2024
Charles Humbert 8
2012-2020
Medical Research Council
2009-2012
MRC Laboratory of Molecular Biology
2009-2012
Bicycle Therapeutics (United Kingdom)
2012
State University of New York
2004
SUNY Downstate Health Sciences University
2004
Cyclic peptides can bind challenging disease targets with high affinity and specificity, offering enormous opportunities for addressing unmet medical needs. However, as biological drugs, most cyclic cannot be applied orally because they are rapidly digested and/or display low absorption in the gastrointestinal tract, hampering their development therapeutics. In this study, we developed a combinatorial synthesis screening approach based on sequential cyclization one-pot peptide acylation...
From a large combinatorial library of chemically constrained bicyclic peptides we isolated selective and potent (K(i) = 53 nM) inhibitor human urokinase-type plasminogen activator (uPA) crystallized the complex. This revealed an extended structure peptide with both loops engaging target to form interaction surface 701 Å(2) multiple hydrogen bonds complementary charge interactions, explaining high affinity specificity inhibitor. The interface resembles that between two proteins suggests these...
ConspectusCyclic peptides can bind to protein targets with high affinities and selectivities, which makes them an attractive modality for the development of research reagents therapeutics. Additional properties, including low inherent toxicity, efficient chemical synthesis, facile modification labels or immobilization reagents, increase their attractiveness. Cyclic peptide ligands against a wide range have been isolated from natural sources such as bacteria, fungi, plants, animals. Many are...
Well established as well recently developed strategies to prevent the fast clearance of peptide drugs from circulation are reviewed.
Abstract Bicyclic peptides generated through directed evolution by using phage display offer an attractive ligand format for the development of therapeutics. Being nearly 100‐fold smaller than antibodies, they promise advantages such as access to chemical synthesis, efficient diffusion into tissues, and needle‐free application. However, unlike do not have a folded structure in solution thus bind less well. We developed bicyclic with hydrophilic structures at their center promote noncovalent...
The rapid renal clearance of peptides in vivo limits this attractive platform for the treatment a broad range diseases that require prolonged drug half-lives. An intriguing approach extending peptide circulation times works through 'piggy-back' strategy which bind via ligand to long-lived serum protein albumin. In accordance with strategy, we developed an easily synthesized albumin-binding based on peptide-fatty acid chimera has high affinity human albumin (Kd=39 nM). This prolongs...
Inhibiting thrombosis without generating bleeding risks is a major challenge in medicine. A promising solution may be the inhibition of coagulation factor XII (FXII), because its knock-out or animals reduced causing abnormal bleeding. Herein, we have engineered macrocyclic peptide inhibitor activated FXII (FXIIa) with sub-nanomolar activity (Ki = 370 ± 40 pM) and high stability (t1/2 > 5 days plasma), allowing for preclinical evaluation first synthetic FXIIa inhibitor. This 1899 Da molecule,...
Easy access to a wide range of structurally diverse stapled peptides is crucial for the development inhibitors protein-protein interactions. Herein, we report bis-functional hypervalent iodine reagents two-component cysteine-cysteine and cysteine-lysine stapling yielding thioalkyne linkers. This method works with unprotected natural amino acid residues does not require pre-functionalization or metal catalysis. The products are stable purification isolation. Post-stapling modification can be...
The specific reaction of O6-alkylguanine-DNA alkyltransferase (AGT) with O6-benzylguanine (BG) derivatives allows for a labeling AGT fusion proteins chemically diverse compounds in living cells and vitro. efficiency the depends on number factors, most importantly reactivity, selectivity stability AGT. Here, we report use directed evolution two different selection systems to further increase activity towards BG by factor 17 demonstrate advantages this mutant displayed surface mammalian cells....
Abstract Combinatorial libraries of structurally diverse peptide macrocycles offer a rich source for the development high‐affinity ligands to targets interest. In this work we have developed linkers generation genetically encoded bicyclic peptides and tested whether cyclised by them significant variations in their backbone conformations. Two new cyclisation reagents, each containing three thiol‐reactive groups, efficiently selectively linear cysteine moieties. When mesitylene linker PK15,...
Bicyclic peptide ligands were found to have good binding affinity and target specificity. However, the method applied generate bicyclic based on phage-peptide alkylation is technically complex limits its application specialized laboratories. Herein, we report a that involves simpler more robust procedure additionally allows screening of structurally diverse libraries. In brief, phage-encoded combinatorial libraries format X(m)CX(n)CX(o)CX(p) are oxidized connect two pairs cysteines (C). This...
A new NMR method for the study of ligand-protein interactions exploits unusual lifetimes long-lived states (LLSs). The provides better contrast between bound and free ligands requires a protein-ligand ratio ca. 25 times lower than established T(1ρ) methods, thus saving on costly proteins. LLS was applied to screening inhibitors urokinase-type plasminogen activator (uPA), which is prototypical target cancer research. With only 10 μM protein, dissociation constant (K(D)) 180 ± 20 nM determined...
High-throughput sequencing was previously applied to phage-selected peptides in order gain insight into the abundance and diversity of isolated peptides. Herein we developed a procedure efficiently compare sequences large numbers for purpose identifying target-binding peptide motifs. We analyze bicyclic against five different protein targets: sortase A, urokinase-type plasminogen activator, coagulation factor XII, plasma kallikrein streptavidin. optimized sequence data filters reduce biases...
Photoswitchable ligands are powerful tools to control biological processes at high spatial and temporal resolution. Unfortunately, such exist only for a limited number of proteins their development by rational design is not trivial. We have developed an in vitro evolution strategy generate light-activatable peptide targets choice. In brief, random peptides were encoded phage display, chemically cyclized with azobenzene linker, exposed UV light switch the into cis conformation, panned against...