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Progress towards the identification of new aggrecanase inhibitors
Francesca De Rienzo1, Puneet Saxena, Federico Filomia
1Department of Chemistry, University of Modena and Reggio Emilia, Via G. Campi 183, Modena, Italy.
Abstract:
Degenerative diseases are still a challenging issue in clinical therapy; even though in several cases it is possible to treat symptoms, drugs able to block disease progression are lacking at present. Osteoarthritis (OA) and Rheumatoid Arthritis (RA) are degenerative diseases leading to serious cartilage destruction, affecting joint functions and giving rise to restricted movement, pain and chronic disability. Current clinical treatment for arthritis is confined to Non Steroidal Anti-Inflammatory Drugs (NSAIDs), which are effective in treating symptoms but fail to block the progression of the disease. Matrix Metalloproteases (MMPs) inhibitors have been clinically studied as possible drugs for cartilage degradation prevention. However, their clinical use has been limited by severe side-effects. Aggrecan, which plays a fundamental role in maintaining the structural and mechanical properties of cartilage, has recently been found to be specifically cleaved by "aggrecanases". Aggrecanases are multidomain zinc metalloproteases, different from MMPs, which cleave the aggrecan within the interglobular domain (IGD). Aggrecan breakdown at this site has been found to be crucial for cartilage degradation. These new findings re-addressed the interest of the research for new arthritis therapeutic agents focusing on aggrecanases rather than on MMPs. This review is meant to provide a critical appraisal of the ongoing developments of Zn-chelating and non chelating aggrecanase inhibitors, with a particular emphasis on the related structure-activity relationships (SARs), in the light of the protein structural information recently made available.
Insights
New aggrecanase inhibitors show promise for treating degenerative joint diseases like osteoarthritis and rheumatoid arthritis by targeting cartilage destruction, unlike current symptom-focused treatments.
Area of Science:
- Biochemistry
- Pharmacology
- Rheumatology
Background:
- Degenerative joint diseases, including osteoarthritis (OA) and rheumatoid arthritis (RA), cause significant cartilage destruction and disability.
- Current treatments like NSAIDs manage symptoms but do not halt disease progression.
- Matrix Metalloproteases (MMPs) inhibitors have shown limited clinical success due to side effects.
Purpose of the Study:
- To critically review the development of aggrecanase inhibitors for treating cartilage degradation in degenerative joint diseases.
- To emphasize structure-activity relationships (SARs) of these inhibitors in light of recent protein structural data.
Main Methods:
- Literature review of aggrecanase inhibitors, focusing on Zn-chelating and non-chelating compounds.
- Analysis of structure-activity relationships (SARs).
- Consideration of recently available protein structural information.
Main Results:
- Aggrecanases, distinct from MMPs, specifically cleave aggrecan at a critical site for cartilage breakdown.
- Aggrecanase inhibitors represent a promising therapeutic strategy for blocking disease progression.
- Structure-activity relationship studies are crucial for designing effective and safe aggrecanase inhibitors.
Conclusions:
- Targeting aggrecanases offers a novel approach to combatting cartilage destruction in OA and RA.
- Further development of aggrecanase inhibitors, guided by structural biology, is essential for future arthritis therapies.
