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Media type:
E-Article
Title:
Structure/activity relationship of eel calcitonin : A study using a newly devised method for designing analogs
:
A study using a newly devised method for designing analogs
Description:
<jats:p>A series of analogs of eel calcitonin (eCT) was synthesized according to a newly devised scheme, ‘the insertion‐inactivation method’, to clarify the structure/activity relationship of a given peptide. This method consists of two steps: the deletion of a residue of the peptide is first chosen and then a series of analogs with the residue reinserted into serial positions is synthesized and biological activities are assessed in each step.</jats:p><jats:p>An analog lacking Lys18 (dK), selected as a deleted analog for the first step, showed marked loss of activities determined by inhibition of <jats:sup>125</jats:sup>I‐eCT binding, growth inhibition, and cAMP production in a porcine kidney cell line LLC‐PK<jats:sub>1</jats:sub>. Activities of a set of 20 analogs with the reinserted lysine residue at serial positions from 12 to 32 (K12–K32) were then evaluated. The results showed the following three patterns of the expression of activities according to the position of the reinsertion: (a) analogs K12–K16 (positions 12–16) and K25 (position 25) showed lower activities than eCT in all assays; (b) K17–K24 (positions 17–24) showed slightly lower activities than eCT in the receptor binding and the growth inhibition and similar level in cAMP production; (c) K26–K32 (positions 26–32) showed considerably lower activities in the former two assays and slightly lower activity in cAMP production. Further, analogs considerably less active than eCT showed unchanged <jats:italic>α</jats:italic>‐helix contents and destroyed amphiphilicity by the insertion of a lysine residue, indicating that amphiphilicity is one of important factors for expressing the activity.</jats:p><jats:p>The results obtained here lead to a conclusion on the significance of each region of eCT molecule as follows: (a) the presence of Lys18 is necessary for the complete expression of biological activity; (b) the length of amphiphilic <jats:italic>α</jats:italic>‐helix to be required for the activity is at most 10 residues ranging from position 8 to position 17; (c) the receptor binding region is located within 9 residues ranging from position 24 to position 32.</jats:p>