De novo discovery of cyclic peptide inhibitors of IL-11 signaling.

Interleukin-11 (IL-11), a member of the IL-6 cytokine family, has potential pro-inflammatory and pro-fibrotic roles in pulmonary, hepatic, cardiovascular, renal and intestinal disease pathogenesis, including oncogenesis. The potential for therapeutic intervention in these disease spaces has therefore made the IL-11 signaling axis an attractive target in drug discovery, and antibody inhibitors of IL-11 signaling are currently under evaluation in Phase I/II clinical trials. While lower molecular weight small molecule and peptide inhibitors may offer the potential for improved tissue penetration, developability and manufacturing cost compared with a protein therapeutic, reports of such chemical matter in the literature are limited.

Genetically-encoded discovery of proteolytically stable bicyclic inhibitors for morphogen NODAL.

In this manuscript, we developed a two-fold symmetric linchpin () that converts readily available phage-displayed peptides libraries made of 20 common amino acids to genetically-encoded libraries of bicyclic peptides displayed on phage. combines an aldehyde-reactive group and two thiol-reactive groups; it bridges two side chains of cysteine [C] with an N-terminal aldehyde group derived from the N-terminal serine [S], yielding a novel bicyclic topology that lacks a free N-terminus. Phage display libraries of SXCXXXXXXC sequences, where X is any amino acid but Cys, were converted to a library of bicyclic -[S]X[C]XXXXXX[C] peptides in 45 ± 15% yield.

Novel High-Throughput Strategy for the Aqueous Solubility Assessment of Peptides and Proteins Exhibiting a Propensity for Gelation: Application to the Discovery of Novel Antibacterial Teixobactin Analogues.

A novel high-throughput aqueous solubility assay was developed for peptides and proteins exhibiting a high gelling propensity (in this case, antibacterial teixobactin analogues). By integrating the assessment of gel formation, as indicated by an increase in the solution viscosity, into the peptide equilibrium solubility screening assay, we were able to estimate the "free-flowing solubility", which is defined as the concentration at which the peptide solution not only is fully dissolved but also is a liquid exhibiting ideal flowing characteristics. In this workflow, peptide solutions passing the turbidity assessment were further screened by viscosity measurements based on nanobead-assisted dynamic light scattering analysis in a 96-well plate.

Dissecting the Binding Interactions of Teixobactin with the Bacterial Cell-Wall Precursor Lipid II.

The prevalence of life-threatening, drug-resistant microbial infections has challenged researchers to consider alternatives to currently available antibiotics. Teixobactin is a recently discovered "resistance-proof" antimicrobial peptide that targets the bacterial cell wall precursor lipid II. In doing so, teixobactin exhibits potent antimicrobial activity against a wide range of Gram-positive organisms.

The Current State of Peptide Drug Discovery: Back to the Future?

Over the past decade, peptide drug discovery has experienced a revival of interest and scientific momentum, as the pharmaceutical industry has come to appreciate the role that peptide therapeutics can play in addressing unmet medical needs and how this class of compounds can be an excellent complement or even preferable alternative to small molecule and biological therapeutics. In this Perspective, we give a concise description of the recent progress in peptide drug discovery in a holistic manner, highlighting enabling technological advances affecting nearly every aspect of this field: from lead discovery, to synthesis and optimization, to peptide drug delivery. An emphasis is placed on describing research efforts to overcome the inherent weaknesses of peptide drugs, in particular their poor pharmacokinetic properties, and how these efforts have been critical to the discovery, design, and subsequent development of novel therapeutics.

Characterization of monoclonal antibodies by a fast and easy liquid chromatography-mass spectrometry time-of-flight analysis on culture supernatant.

Rapid and efficient structural analysis is key to the development of new monoclonal antibodies. We have developed a fast and easy process to obtain mass spectrometry profiles of antibodies from culture supernatant. Treatment of the supernatant with IdeS generates three fragments of 25 kDa that can be analyzed by liquid chromatography-mass spectrometry time-of-flight (LC-MS TOF) in one run: LC, Fd, and Fc/2.

Drug-to-genome-to-drug, step 2: reversing selectivity in a series of antiplasmodial compounds.

In a recent paper, we have described the discovery of antimalarial compounds derived from tadalafil, using a drug-to-genome-to-drug approach ( J. Med. Chem.