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Digestive System Disorders

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Synthetic peptide

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C5AR1 x C5AR2	1

BACKGROUND AND PURPOSE A 3H‐labelled derivative of the novel small‐molecule bradykinin (BK) B2 receptor antagonist JSM10292 was used to directly study its binding properties to human and animal B2 receptors in intact cells and to closely define its binding site.EXPERIMENTAL APPROACH Equilibrium binding, dissociation and competition studies with various B2 receptor ligands and [3H]‐JSM10292 were performed at 4°C and 37°C. The experiments were carried out using HEK293 cells stably (over)expressing wild‐type and mutant B2 receptors of human and animal origin.KEY RESULTS [3H]‐JSM10292 bound to B2 receptors at 4°C and at 37°C with the same high affinity. Its dissociation strongly depended on the temperature and increased when unlabelled B2 receptor agonists or antagonists were added. [3H]‐JSM10292 is cell membrane‐permeant and thus also bound to intracellular, active B2 receptors, as indicated by the different ‘nonspecific’ binding in the presence of unlabelled JSM10292 or of membrane‐impermeant BK. Equilibrium binding curves with [3H]‐JSM10292 and competition experiments with unlabelled JSM10292 and [3H]‐BK showed a different affinity profile for the wild‐type B2 receptor in different species (man, cynomolgus, rabbit, mouse, rat, dog, pig, guinea pig). Characterization of B2 receptor mutants and species orthologues combined with homology modelling, using the CXCR4 as template, suggests that the binding site of JSM10292 is different from that of BK but overlaps with that of MEN16132, another small non‐peptide B2 receptor ligand.CONCLUSIONS AND IMPLICATIONS [3H]‐JSM10292 is a novel, cell membrane‐permeant, high‐affinity B2 receptor antagonist that allows direct in detail studies of active, surface and intracellularly located wild‐type and mutant B2 receptors.

01 May 2011·Medical Microbiology and ImmunologyQ4 · MEDICINE

Characterisation of the epitope for a herpes simplex virus glycoprotein B-specific monoclonal antibody with high protective capacity

Q4 · MEDICINE

Article

Author: Martin P. Däumer ; Doris M. Giesen ; Bertfried Matz ; Karl E. Schneweis ; Sheriff Aziz ; Beate Schneider ; Ulrich Reineke ; Bernd Kupfer ; Jens Schneider-Mergener ; Rolf Kaiser ; Anna M. Eis-Hübinger

Monoclonal antibody (MAb) 2c, specific for glycoprotein B of herpes simplex virus (HSV), had been shown to mediate clearance of infection from the mucous membranes of mice, thereby completely inhibiting mucocutaneous inflammation and lethality, even in mice depleted of both CD4(+) and CD8(+) cells. Additionally, ganglionic infection was highly restricted. In vitro, MAb 2c exhibits a potent complement-independent neutralising activity against HSV type 1 and 2, completely inhibits the viral cell-to-cell spread as well as the syncytium formation induced by syncytial HSV strains (Eis-Hübinger et al. in Intervirology 32:351-360, 1991; Eis-Hübinger et al. in J Gen Virol 74:379-385, 1993). Here, we describe the mapping of the epitope for MAb 2c. The antibody was found to recognise a discontinuous epitope comprised of the HSV type 1 glycoprotein B residues 299 to 305 and one or more additional discontinuous regions that can be mimicked by the sequence FEDF. Identification of the epitope was confirmed by loss of antibody binding to mutated glycoprotein B with replacement of the epitopic key residues, expressed in COS-1 cells. Similarly, MAb 2c was not able to neutralise HSV mutants with altered key residues, and MAb 2c was ineffective in mice inoculated with such mutants. Interestingly, identification and fine-mapping of the discontinuous epitope was not achieved by binding studies with truncated glycoprotein B variants expressed in COS cells but by peptide scanning with synthetic overlapping peptides and peptide key motif analysis. Reactivity of MAb 2c was immensely increased towards a peptide composed of the glycoprotein B residues 299 to 305, a glycine linker, and a C-terminal FEDF motif. If it could be demonstrated that antibodies of the specificity and bioactivity of MAb 2c can be induced by the epitope or a peptide mimicking the epitope, strategies for active immunisation might be conceivable.

22 Nov 2010·Angewandte Chemie

Konformative Kontrolle über Integrin‐Subtyp‐Selektivitäten in isoDGR‐Peptidmotiven: ein biologischer Schalter

Author: Grit Zahn ; Dörte Vossmeyer ; Roland Stragies ; Elke Otto ; Luciana Marinelli ; Andreas O. Frank ; Herbert B. Schiller ; Carlos Mas‐Moruno ; Ettore Novellino ; Horst Kessler ; Alexander Bochen ; Sandro Cosconati

1

News (Medical) associated with Jerini

22 Aug 2022

·endpts.com

Pharvaris hits a snag with hereditary angioedema pill as FDA places hold on trials

Swiss biotech Pharvaris announced Monday that the FDA has placed a hold on the clinical trials for its oral drug PHA121 which aims at treating hereditary angioedema, or HAE, a rare genetic condition. The regulators placed the hold after reviewing the company’s nonclinical data, Pharvaris said. The FDA’s decision is a setback for the company’s Phase II study, which aims to evaluate the efficacy and safety of the drug. Pharvaris is among the few companies to develop an oral drug for HAE, a disease characterized by painful swelling in hands, feet, and occasionally in the airways or intestinal walls. While effective therapies already exist, such as CSL’s Haegarda and Takeda’s Cinryze, Takhzyro and Firazyr, all of them are injectables. HAE is caused by a deficiency in the blood plasma protein C1 esterase inhibitor, and both Haegarda and Cinryze try to boost the level of that protein in the blood. Firazyr, on the other hand, blocks bradykinin, a blood protein that is overproduced in HAE because of increased levels of C1. Elevated levels of bradykinin cause blood cells to leak and tissues to swell. Pharvaris’ drug PHA121 is an oral pill that works as a bradykinin B2 receptor antagonist. Phase I data from 16 healthy volunteers suggest their molecule is 24 times as potent as Firazyr, and the company has already launched two Phase II trials: one for prophylaxis and one for treating acute pain. Other companies have tried to develop oral therapies for HAE in the past but have not found great success. BioCryst’s oral drug BCX7353 passed a Phase III trial, with the higher dose reducing the angioedema attack rate by 44% versus placebo (p<0.001), while the lower dose cut the attack rate by 30% (p=0.024). However, analysts were left unimpressed after suggesting that at least a 50% reduction of attack rate would ensure BCX7353 would be competitive. Meanwhile, Pharvaris CEO Berndt Modig said the company was working closely with the FDA to address the agency’s concerns. The company’s stock $PHVS fell nearly 20% on Monday after the company announced the hold. Pharvaris was founded by Modig, and other veterans from Jerini, the biotech that originally developed Firazyr. In November 2020, the company raised an $80 million Series C led by Viking Global Investors and General Atlantic.

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Pipeline Snapshot as of 20 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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