PROBLEM TO BE SOLVED: To provide crosslinked polypeptides that possess reduced affinity to serum proteins to permit good activity in the presence of serum, while still retaining sufficient affinity to the cell membranes to be transported into the cell, retaining sufficient affinity to serum proteins to have acceptable pharmacokinetics, and retaining high affinity binding to target receptor(s) within the cell; and to provide methods for optimizing the same.SOLUTION: This invention relates to: biologically active crosslinked polypeptides; and further methods for identifying and preparing the improved polypeptides. In one embodiment, a method of identifying cross-linked polypeptides with improved efficacies in human whole blood comprises the steps of: synthesizing analogs of the parent cross-linked polypeptide; and performing cellular assays in the absence of human serum proteins and also in the presence of one or more concentrations of human serum, so as to determine the apparent affinity of each cross-linked polypeptide for human serum proteins.
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