A5056535981- Complement system in diseases
- Monoclonal and Polyclonal Antibodies Research
- Peptidase Inhibition and Analysis
- Enzyme Structure and Function
- Virus-based gene therapy research
- Chemical Synthesis and Analysis
- Viral Infectious Diseases and Gene Expression in Insects
- Blood Coagulation and Thrombosis Mechanisms
- Synthesis and Characterization of Heterocyclic Compounds
- Computational Drug Discovery Methods
- Biochemical and Molecular Research
- Erythrocyte Function and Pathophysiology
- Asymmetric Synthesis and Catalysis
- Crystallization and Solubility Studies
- Protein purification and stability
- Porphyrin and Phthalocyanine Chemistry
- Carbohydrate Chemistry and Synthesis
- Neuropeptides and Animal Physiology
- Synthetic Organic Chemistry Methods
- bioluminescence and chemiluminescence research
- Adenosine and Purinergic Signaling
- Toxin Mechanisms and Immunotoxins
- Platelet Disorders and Treatments
- Diabetes Treatment and Management
- Blood groups and transfusion
Idorsia (Switzerland)
2018-2025
Novartis (Switzerland)
2008-2020
Novartis Institutes for BioMedical Research
2008-2019
Actelion (Switzerland)
2016
University of Zurich
2003
Ollscoil na Gaillimhe – University of Galway
1999-2000
Lehman College
1975
University of Geneva
1971-1972
Dysregulation of the alternative complement pathway (AP) predisposes individuals to a number diseases including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and C3 glomerulopathy. Moreover, glomerular Ig deposits can lead complement-driven nephropathies. Here we describe discovery highly potent, reversible, selective small-molecule inhibitor factor B, serine protease that drives central amplification loop AP. Oral administration prevents KRN-induced arthritis in...
To identify starting points for therapeutics targeting SARS-CoV-2, the Paul Scherrer Institute and Idorsia decided to collaboratively perform an X-ray crystallographic fragment screen against its main protease. Fragment-based screening was carried out using crystals with a pronounced open conformation of substrate-binding pocket. Of 631 soaked fragments, total 29 hits bound either in active site (24 hits), remote binding pocket (three hits) or at crystal-packing interfaces (two hits)....
The alternative pathway (AP) of the complement system is a key contributor to pathogenesis several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. serine protease factor B (FB) node in AP integral formation C3 C5 convertase. Despite prominent role FB AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we...
The nucleation event in protein crystallization is a part of the process that poorly controlled. It generally accepted should be metastable phase for crystal growth, but higher levels saturation are needed. Formation nuclei bulk solvent requires interaction molecules until critical size aggregate created. In many experiments sufficiently high not reached to allow this occur. If an environment can created favours local concentration macromolecules, energy barrier may lowered. When seeds...
Dipeptidyl peptidase IV is a multifunctional type II transmembrane serine protease glycoprotein. The high-resolution crystal structure of the homodimeric human apo dipeptidyl has been determined at 1.9 A resolution. In addition, binary complex with 1-[([2-[(5-iodopyridin-2-yl)amino]-ethyl]amino)-acetyl]-2-cyano-(S)-pyrrolidine solved, revealing nature covalent interaction active-site serine.
Galectin‐3 (Gal‐3), a β‐galactoside‐binding lectin, is implicated in diverse cellular functions ranging from immune response modulation to tissue homeostasis. Notably, increased Gal‐3 expression has been linked the progression of numerous diseases, including cancer, fibrosis, and cardiovascular disorders, underscoring its potential as therapeutic target. Small molecule inhibitors have discovered are valuable tools study such diseases. We report here discovery novel, galactose‐based, small...
In this study, we performed the hit-to-lead optimization of a SARS-CoV-2 Mpro diazepane hit (identified by computational methods in previous work) combining simulations with high-throughput medicinal chemistry (HTMC). Leveraging 3D structural information Mpro, refined original targeting S1 and S2 binding pockets protein. Additionally, identified novel exit vector pointing toward S1' pocket, which significantly enhanced affinity. This strategy enabled us to transform, rapidly limited number...
In this study, characterization and optimization of a modified microbatch crystallization technique has been attempted in order to provide rapid screening method. Using method for certain advantages over standard vapour-diffusion methods: no sealing drops is required, reservoir solutions are needed the experiments can easily be performed range temperatures.
UDP-3-O-((R)-3-hydroxymyristoyl)-N-glucosamine deacetylase (LpxC) is as an attractive target for the discovery and development of novel antibacterial drugs to address critical medical need created by multidrug resistant Gram-negative bacteria. By using a scaffold hopping approach on known family methylsulfone hydroxamate LpxC inhibitors, several hit series eliciting potent activities against Enterobacteriaceae Pseudomonas aeruginosa were identified. Subsequent hit-to-lead optimization,...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of disease (COVID-19) since its emergence in December 2019. As January 2024, there been over 774 million reported cases and 7 deaths worldwide. While vaccination efforts have successful reducing the severity decreasing transmission rate, development effective therapeutics against SARS-CoV-2 remains critical need. The main protease (Mpro) is an essential enzyme required for viral replication identified...
Methylation of octaethylporphin with methyl iodide yields the 21,22-dimethylporphin as well 21-monomethyl derivative. The structure salt (trans arrangement groups) is assigned from n.m.r. data evidence for chirality provided by partial resolution corresponding D-camphorsulphonate. fluorosulphonate gives 21,23-dimethylporphin fluorosulphonate, probably through intermediacy 21,22,23-trimethylporphin salt, suggesting that 21- and 23-methyl substituents are cis-oriented. Octaethylchlorin...
Ring contraction of cyclo-octatetraene epoxide to cycloheptatriene-7-aldehyde occurs at –50° in the presence rhodium(I) and further rearrangement higher temperatures, whilst carbon series bicyclo[6,1,0]nonatriene its 9,9-dimethyl derivative undergo stereospecific rearrangement, rhodium(I), corresponding cis-8,9-dihydroindenes.
The highly specific S1 serine protease factor D (FD) plays a central role in the amplification of complement alternative pathway (AP) innate immune system. Genetic associations humans have implicated AP activation age-related macular degeneration (AMD), and dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) atypical hemolytic uremic syndrome (aHUS). combination structure-based hit identification subsequent optimization center (S)-proline-based...
High-resolution crystal structures of Staphylococcus aureus methionine aminopeptidase I in complex with various keto heterocycles and aminoketones were determined, the intermolecular ligand interactions enzyme are reported. The compounds effective inhibitors S. because formation an uncleavable tetrahedral intermediate upon binding. electron densities unequivocally show enzyme-catalyzed transition-state analogue mimicking that for amide bond hydrolysis substrates.
The cysteine protease adenain is the essential of adenovirus and, as such, represents a promising target for treatment ocular and other adenoviral infections. Through concise two-pronged hit discovery approach we identified tetrapeptide nitrile 1 pyrimidine 2 complementary starting points inhibition. These hits enabled first high-resolution X-ray cocrystal structures with inhibitors bound revealed binding mode 2. screening were optimized by structure-guided medicinal chemistry strategy into...
Abstract Reduction of 2‐phenyl‐ and 2‐methyl‐ exo ‐3,4‐dichlorobicyclo[3.2.1]oct‐2‐enes with lithium aluminium hydride (LAH) or tributyltin (TBTH) gave endo ‐2‐phenyl‐3‐chlorobicyclo[3.2.1]oct‐3‐ene, 2‐phenyl‐3‐chlorobicyclo[3.2.1]oct‐2‐ene their methyl analogues. The action both reagents on ‐3, 4‐dibromobicyclo[3.2.1]oct‐2‐ene similarly resulted in reductive monodebromination to give normal allylically rearranged products. Additionally, further reduction occurred...
Chronic dysregulation of alternative complement pathway activation has been associated with diverse clinical disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinurea. Factor D is a trypsin-like serine protease narrow specificity for arginine in the P1 position, which catalyzes first enzymatic reaction amplification loop pathway. In this article, we describe two hit finding approaches leading to discovery new chemical matter pivotal system: silico active...
The use of the tellurium-centered Anderson−Evans polyoxotungstate [TeW6O24]6− (TEW) as a crystallization additive has been described. Here, we present TEW an in screening nucleotide binding domain (NBD) HSP70. Crystallization HSP70 NBD absence using standard commercial screen resulted single crystal form. An identical presence both “TEW free” form and additional with different packing. was observed forms, either well-defined molecule or overlapping alternate positions suggesting...