Low-molecular weight inhibitors of the alternative complement pathway

Area of Science:

• Immunology
• Pharmacology

Background:

• The alternative complement pathway is implicated in various severe diseases, including paroxysmal nocturnal hemoglobinuria and age-related macular degeneration.
• Dysregulation of this pathway, caused by genetic factors or antibodies, drives disease progression.
• Its amplification role in all complement pathways suggests involvement in a broader range of conditions.

Purpose of the Study:

• To identify and develop specific inhibitors of the alternative complement pathway for therapeutic applications.
• To overcome challenges in targeting the pathway's central proteases, factor B and factor D.

Main Methods:

• Focus on drug discovery efforts targeting factor B and factor D.
• Development of potent and selective low-molecular weight (LMW) oral inhibitors.

Main Results:

• Successful discovery of LMW oral inhibitors for both factor B and factor D.
• Several inhibitor molecules are currently in clinical development for complement-mediated diseases.

Conclusions:

• Low-molecular weight inhibitors offer a promising therapeutic strategy for complement-mediated diseases.
• These inhibitors may also be applicable to neurodegenerative diseases involving complement activation in the central nervous system.