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Be on Target: Strategies of Targeting Alternative and Lectin Pathway Components in Complement-Mediated Diseases
József Dobó1, Andrea Kocsis1, Péter Gál1
1Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
Insights
The complement system, implicated in rare and common diseases, is a key drug development target. Targeting lectin and alternative pathways, particularly MASP proteases, offers new therapeutic strategies.
Area of Science:
- Immunology
- Pharmacology
- Molecular Biology
Background:
- The complement system's dysregulation is linked to numerous diseases, including rare genetic disorders and common multifactorial conditions like myocardial infarction and neurodegenerative diseases.
- Recent research highlights the complement system's critical role in both primary complement-mediated diseases and complex multifactorial conditions.
Purpose of the Study:
- To review the therapeutic potential of targeting various complement system components, focusing on the lectin pathway (LP) and alternative pathway (AP).
- To explore novel drug development strategies based on the intricate cross-talk between the LP and AP.
Main Methods:
- Review of current literature on complement system pathways and their therapeutic targeting.
- Analysis of the roles of specific complement proteins, including serine proteases (MASP-1/2/3, factor D, factor B), pattern recognition molecules, and regulatory components.
- Examination of recent discoveries regarding the interplay between LP and AP.
Main Results:
- Serine proteases (MASP-1/2/3, factor D, factor B), pattern recognition molecules, regulatory proteins (factor H, I, properdin), and C3 are identified as potential drug targets.
- Emerging evidence reveals that mannan-binding lectin-associated serine proteases (MASPs) are crucial for both LP and AP activation.
- MASP-3 is identified as a key enzyme supplying factor D for AP activation, positioning it as a novel therapeutic target. MASP-1 is essential for AP activity on surfaces like Gram-negative bacteria.
Conclusions:
- Targeting components of the complement system, particularly the LP and AP, holds significant promise for treating a wide range of diseases.
- Understanding the cross-talk between LP and AP, especially the role of MASPs, opens new avenues for developing innovative complement-targeted therapies.
- MASP-3 represents a promising new target for modulating AP activity, offering potential therapeutic benefits for complement-related disorders.
Abstract:
The complement system has moved into the focus of drug development efforts in the last decade, since its inappropriate or uncontrolled activation has been recognized in many diseases. Some of them are primarily complement-mediated rare diseases, such as paroxysmal nocturnal hemoglobinuria, C3 glomerulonephritis, and atypical hemolytic uremic syndrome. Complement also plays a role in various multifactorial diseases that affect millions of people worldwide, such as ischemia reperfusion injury (myocardial infarction, stroke), age-related macular degeneration, and several neurodegenerative disorders. In this review, we summarize the potential advantages of targeting various complement proteins with special emphasis on the components of the lectin (LP) and the alternative pathways (AP). The serine proteases (MASP-1/2/3, factor D, factor B), which are responsible for the activation of the cascade, are straightforward targets of inhibition, but the pattern recognition molecules (mannose-binding lectin, other collectins, and ficolins), the regulatory components (factor H, factor I, properdin), and C3 are also subjects of drug development. Recent discoveries about cross-talks between the LP and AP offer new approaches for clinical intervention. Mannan-binding lectin-associated serine proteases (MASPs) are not just responsible for LP activation, but they are also indispensable for efficient AP activation. Activated MASP-3 has recently been shown to be the enzyme that continuously supplies factor D (FD) for the AP by cleaving pro-factor D (pro-FD). In this aspect, MASP-3 emerges as a novel feasible target for the regulation of AP activity. MASP-1 was shown to be required for AP activity on various surfaces, first of all on LPS of Gram-negative bacteria.
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