What question did this study set out to answer?

To engineer a potent, pure antagonist of PTH and PTHrP by removing partial agonism from PTHrP(7-34)NH2 while maintaining or improving antagonist potency.

July 1, 1990Endocrinology

Removal Op Partial Aoonism Prom Parathyroid Hormone (Pth)-Related Protein-(7-34)nh2by Substitution Op PTH Amino Acids at Positions 10 and 11

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Authors

RNRuth F. NuttMerck & Co., Inc., Rahway, NJ, USA (United States)MCMichael P. CaulfieldUniversity of Washington JLJay J. LevyNovo Nordisk (United States)

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Implication

In vitro study reveals elimination of partial agonism and enhanced antagonist potency in bone cells, indicating the role of residues 10-12 in receptor activation.

Key Points

To engineer a potent, pure antagonist of PTH and PTHrP by removing partial agonism from PTHrP(7-34)NH2 while maintaining or improving antagonist potency.
Substituted native PTH amino acids Asn10 and Leu11 into PTHrP(7-34)NH2 and [D-Trp12]PTHrP(7-34)NH2, and performed reciprocal insertion of Asp10 and Lys11 into [Tyr34]hPTH(7-34)NH2.
Evaluated adenylate cyclase activation and antagonist potency in ROS 17/2.8 cells, including sensitized cells pretreated with dexamethasone and pertussis toxin.
[Asn10,Leu11]- and [Asn10,Leu11,D-Trp12]-PTHrP(7-34)NH2 exhibited 23- and 26-fold higher antagonist potency than their parent analogs, respectively, with zero detectable partial agonism even in sensitized cells.
Inserting PTHrP residues Asp10 and Lys11 into [Tyr34]hPTH(7-34)NH2 reduced antagonist potency by more than 6-fold and generated agonist activity.

Cite This Study

Nutt et al. (1990) studied this question.

synapsesocial.com/papers/6a8665fd169aec2a7f0f738d https://doi.org/10.1210/endo-127-1-491

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Implication

In vitro study reveals elimination of partial agonism and enhanced antagonist potency in bone cells, indicating the role of residues 10-12 in receptor activation.

Removal Op Partial Aoonism Prom Parathyroid Hormone (Pth)-Related Protein-(7-34)nh2by Substitution Op PTH Amino Acids at Positions 10 and 11

Discussion

Member takes

Implication

Key Points

Cite This Study

Removal Op Partial Aoonism Prom Parathyroid Hormone (Pth)-Related Protein-(7-34)nh2by Substitution Op PTH Amino Acids at Positions 10 and 11

Discussion

Member takes

Implication

Key Points

Cite This Study

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