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Systematical mutational analysis of teriparatide on anti-osteoporosis activity by alanine scanning
Haiyan Liang1, Huaxing Shen2, Mengjun Zheng3
1School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; School of Pharmacy, Second Military Medical University, Shanghai 200433, PR China.
Abstract:
Osteoporosis is a progressive systemic skeletal disease that decreases bone density and bone quality, making them fragile and easy to break. In spite of effective anti-osteoporosis potency, teriparatide, the first anabolic medications approved for the treatment of osteoporosis, was proven to exhibit various side effects. And the relevant structure-activity relationship (SAR) of teriparatide was in need. In this work, we performed a systematical alanine scanning against teriparatide and synthesized 34 teriparatide derivatives. Their biological activities were evaluated and the importance of each residue for anti-osteoporosis activity was also revealed. A remarkable decrease in activity was observed for alanine replacement of the residue Gly12, His14, Ser17, Arg20 and Leu24, showcasing the important role of these residues in teriparatide on anti-osteoporosis activity. On contrary, when Gly13 and Gln30 were mutated to Ala, the peptide derivatives exhibited the significantly increased activities, demonstrating that these two residues could be readily replaced. Our research expanded the peptide library of teriparatide analogues and presented a potential opportunity for designing the more powerful anti-osteoporosis peptide agents.
Insights
Researchers explored teriparatide
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Endocrinology
Background:
- Osteoporosis is a skeletal disease characterized by decreased bone density and quality, leading to fragility.
- Teriparatide is an effective anabolic agent for osteoporosis but has associated side effects.
- Understanding the structure-activity relationship (SAR) of teriparatide is crucial for developing improved treatments.
Purpose of the Study:
- To systematically investigate the SAR of teriparatide through alanine scanning.
- To identify key residues essential for teriparatide's anti-osteoporosis activity.
- To discover novel teriparatide analogues with enhanced therapeutic potential.
Main Methods:
- Systematic alanine scanning of teriparatide.
- Synthesis of 34 teriparatide derivatives.
- Evaluation of biological activities of synthesized analogues.
Main Results:
- Alanine replacement of Gly12, His14, Ser17, Arg20, and Leu24 significantly reduced anti-osteoporosis activity.
- Mutations of Gly13 and Gln30 to alanine resulted in significantly increased activity.
- Identified key residues critical for teriparatide's efficacy and residues amenable to modification.
Conclusions:
- Established the importance of specific residues for teriparatide's anti-osteoporosis function.
- Identified Gly13 and Gln30 as key sites for modification to enhance activity.
- Provided a foundation for designing more potent teriparatide-based osteoporosis therapies.
