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Development and Application of Small Molecule-Peptide Conjugates as Cathepsin K-Specific Covalent Irreversible
Gourab Dey1, Evalyn Yakobovich1, Jure Loboda2
1The Institute for Drug Research, The School of Pharmacy, The Faculty of Medicine, The Hebrew University, Jerusalem 9112001, Israel.
Abstract:
Cathepsin K (CTSK), a proteolytic enzyme that degrades the extracellular matrix, is recognized as a significant therapeutic target for osteoporosis, osteoarthritis, and rheumatoid arthritis. Due to adverse effects, no clinically approved drugs exist for CTSK. In order to develop safer therapeutics, highly selective CTSK inhibitors are required to elucidate the origins of side effects. Here, we developed various hybrid inhibitors by combining peptide sequences with small organic molecules. An acyloxymethyl ketone electrophile was incorporated as a bioisostere of the glycine-glycine cleavage site and inverse peptide sequences to enhance prime site interactions, as seen in the crystal structure. Additionally, a diphenyl group was incorporated to improve nonprime site interactions, culminating in highly selective and potent irreversible CTSK inhibitors with negligible off-target binding by closely related cathepsins. These novel inhibitors were also designed to attach to targeting moieties, further reducing off-target effects in vivo. Our findings demonstrate that these highly selective inhibitors are nontoxic, effectively inhibit bone resorption by human osteoclasts, block CTSK activity in cells and their nuclei, and inhibit activity in human lung cancer tissue. This study highlights significant advancements in designing CTSK inhibitors with potential clinical applications for lung cancer and osteoclast-related conditions.
Insights
New hybrid inhibitors targeting Cathepsin K (CTSK) show high selectivity and potency, offering potential treatments for osteoporosis, arthritis, and lung cancer with reduced side effects.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Pharmacology
Background:
- Cathepsin K (CTSK) is a key enzyme in extracellular matrix degradation and a therapeutic target for bone diseases.
- Current CTSK inhibitors face challenges due to adverse effects, necessitating the development of highly selective alternatives.
- Understanding CTSK's role is crucial for treating osteoporosis, osteoarthritis, and rheumatoid arthritis.
Purpose of the Study:
- To design and synthesize novel, highly selective Cathepsin K (CTSK) inhibitors.
- To investigate the potential of these inhibitors in treating osteoclast-related conditions and lung cancer.
- To reduce off-target binding and associated adverse effects of CTSK inhibitors.
Main Methods:
- Hybrid inhibitors were developed by combining peptide sequences with small organic molecules.
- Acyloxymethyl ketone electrophile and inverse peptide sequences were incorporated to enhance prime site interactions.
- Diphenyl groups were added to improve nonprime site interactions, and targeting moieties were integrated.
Main Results:
- Novel hybrid inhibitors demonstrated high selectivity and potency against CTSK with negligible off-target binding.
- The inhibitors were found to be nontoxic and effectively inhibited bone resorption by human osteoclasts.
- Inhibition of CTSK activity was observed in cellular and nuclear compartments, as well as in human lung cancer tissue.
Conclusions:
- The developed hybrid inhibitors represent a significant advancement in designing selective CTSK inhibitors.
- These novel compounds show promise for clinical applications in osteoclast-related conditions and lung cancer.
- The strategy of incorporating specific chemical moieties enhances inhibitor selectivity and reduces potential side effects.
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