Related Experiment Video

Updated: Jan 27, 2026

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

9.5K

Small-molecule factor B inhibitor for the treatment of complement-mediated diseases

Anna Schubart1, Karen Anderson2,3, Nello Mainolfi2,4

  • 1Novartis Institutes for BioMedical Research, Novartis Pharma AG, CH-4056 Basel, Switzerland.

Proceedings of the National Academy of Sciences of the United States of America
|March 31, 2019
PubMed

Insights

A novel small-molecule inhibitor targeting factor B effectively blocks the alternative complement pathway (AP). This discovery offers a potential new oral therapy for various complement-mediated diseases, including kidney disorders and paroxysmal nocturnal hemoglobinuria.

Area of Science:

  • Immunology
  • Nephrology
  • Pharmacology

Background:

  • The alternative complement pathway (AP) is implicated in various diseases, including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and C3 glomerulopathy.
  • Glomerular immunoglobulin deposits can trigger complement-mediated kidney damage, leading to nephropathies.

Purpose of the Study:

  • To discover and characterize a potent, selective, and reversible small-molecule inhibitor of factor B, a key component of the AP amplification loop.
  • To evaluate the therapeutic potential of this factor B inhibitor in preclinical models of complement-mediated diseases.

Main Methods:

  • Development of a small-molecule inhibitor targeting factor B, a serine protease central to the AP.
  • In vivo studies using KRN-induced arthritis model in mice and a rat model of membranous nephropathy.
  • In vitro assessment of complement activation in patient sera and hemolysis of paroxysmal nocturnal hemoglobinuria erythrocytes.

Main Results:

  • The factor B inhibitor demonstrated efficacy in preventing KRN-induced arthritis in mice.
  • Oral administration showed effectiveness in prophylactic and therapeutic settings for experimental membranous nephropathy in rats.
  • Inhibition of factor B successfully prevented complement activation in C3 glomerulopathy patient sera and reduced hemolysis in PNH erythrocytes.

Conclusions:

  • Factor B inhibition represents a promising therapeutic strategy for systemic treatment of complement-mediated diseases.
  • The developed small-molecule inhibitor shows potential for clinical development in conditions driven by the alternative complement pathway.

Keywords:
alternative pathwaycomplementdrug discoveryfactor Bnephropathy

More Related Videos

Y-90 Radioembolization and PD-1 Inhibitor as Neoadjuvant Treatment in Hepatocellular Carcinoma09:11

Y-90 Radioembolization and PD-1 Inhibitor as Neoadjuvant Treatment in Hepatocellular Carcinoma

Published on: May 24, 2024

1.1K
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia10:49

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia

Published on: September 18, 2013

18.6K

Related Concept Videos

Parkinson's Disease: Treatment01:24

Parkinson's Disease: Treatment

Neurodegenerative disorders, such as Parkinson's Disease (PD), involve the gradual and irreversible destruction of neurons in particular brain areas. These disorders exhibit standard features like proteinopathies, selective vulnerability of some neurons, and an interaction of intrinsic properties, genetics, and environmental influences in neural injury.
Parkinson's Disease is primarily a result of the loss of dopaminergic neurons in the substantia nigra pars compacta. The cornerstone of...
1.0K
Alzheimer's Disease: Treatment01:22

Alzheimer's Disease: Treatment

Alzheimer's Disease (AD), a neurodegenerative disorder, is pathologically identified by amyloid plaques and neurofibrillary tangles composed of tau protein. AD pharmacotherapy aims to manage cognitive symptoms, delay disease progression, and treat behavioral symptoms. The treatment is primarily symptomatic and palliative, with no definitive disease-modifying therapy available. Cholinesterase inhibitors, including donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne), are...
854
Treatment for Pulmonary Arterial Hypertension: Phosphodiesterase Inhibitors01:28

Treatment for Pulmonary Arterial Hypertension: Phosphodiesterase Inhibitors

Phosphodiesterase 5 (PDE5) inhibitors are potent enzymes that function to hydrolyze cyclic nucleotides to their corresponding 5' monophosphates. Their unique biochemical properties have been applied in treating Pulmonary Arterial Hypertension (PAH).
Among the PDE5 inhibitors, sildenafil (Revatio) stands out as a competitive and selective inhibitor. It operates by elevating cellular levels of cGMP and augmenting signaling through the cGMP-PKG pathway, promoting vasodilation. Upon oral...
587
Eukaryotic Transcription Inhibitors01:52

Eukaryotic Transcription Inhibitors

Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
10.9K
Complement System01:27

Complement System

The complement system is a group of approximately 20 plasma proteins that strengthen the body's defenses against infections through opsonization, inflammation, and cell lysis. Opsonization involves coating pathogens with complement proteins, making them more recognizable and facilitating phagocyte engulfment. Certain complement proteins induce inflammation that attracts immune cells to the site of infection. Cell lysis involves the destruction of pathogens through the formation of a...
9.9K
Complementation Tests00:49

Complementation Tests

A complementation test is a simple cross to identify whether the two mutations are located on the same gene or different genes. It was first performed by Edward Lewis in the 1940s while working on fruit flies. He developed the test to identify the location and arrangement of different mutations on chromosomes.
Organisms heterozygous for different mutations are crossed pairwise in all combinations. If present on different genes, the mutations can complement each other by providing the missing...
6.1K