Peptidomimetics of biologically active metallopeptides

A method of deriving a peptidomimetic of a biologically active metallopeptide comprising the steps of:

• (a) selecting a biologically active metallopeptide with a ring structure defining a template space, the metallopeptide being of the formula:
• 206
• wherein
• R1 is at least one natural or unnatural L- or D-amino acid residues and optionally any terminal or capping group;
• R2 and R3 are the same or different and independently selected from an amino acid side chain moiety or derivative thereof;
• R4 is any terminal or capping group and optionally any one or more natural or unnatural L- or D-amino acid residues;
• and
• M is a metal ion;
• (b) providing a non-peptidic ring structure superimposable on the template space defined by at least one ring of the ring structure of the biologically active metallopeptide, the non-peptidic ring structure being of the formula:
• 207
• wherein
• X1 is (CH2)m or X3;
• X2 is independently CH2, CH, NH or N;
• X3 is independently (CH2)n, CH, NH, N, O, C═O, C═S, S, S═O, or SO2;
• n is 0, 1, 2 or 3;
• and
• m is 0 or 1;
• provided that any two adjacent CH groups, adjacent NH and CH groups or adjacent NH groups may optionally form a double bond;
• and
• (c) adding at least three elements R5, R6, and R7, to the non-peptidic ring structure, whereby a peptidomimetic of one of the following formulas results:
• 208
• wherein
• R5 is any moiety other than H;
• R6 is an amino acid side chain moiety or derivative thereof;
• R7 is one or more amino acid residues or derivatives thereof and optionally a terminal group moiety, or is an amino acid side chain moiety or derivative thereof;
• and
• R7 occupies a similar descriptor space as R1 and at least either R6 occupies a similar descriptor space as R2 or R5 occupies a similar descriptor space as R3.

A method of deriving a peptidomimetic that binds to a target of interest comprising the steps of:

• (a) selecting a known amino acid sequence with a known primary structure of n residues, where n is at least 4, which known amino acid sequence binds to the target of interest;
• (b) designing a library of amino acid sequences by selecting at least two consecutive residues from a stretch of consecutive residues in the known primary structure and inserting a residue providing both an N and S for metal ion complexation on the carboxy terminal end of two of the at least two selected consecutive residues, or alternatively selecting at least three consecutive residues from a stretch of consecutive residues in the known primary structure and substituting a residue providing both an N and S for metal ion complexation for the carboxy terminal residue of any consecutive stretch of three of the at least three selected consecutive residues, each such sequence constituting a library member, wherein each library member differs by at least one residue or the location of the insertion of or substitution with the residue providing both an N and S for metal ion complexation;
• (c) constructing the library of designed amino acid sequences;
• (d) complexing each library member of designed amino acid sequences to a metal ion, thereby forming a library of metallopeptides wherein the metal ion is complexed to at least three atoms in the peptide sequence, such at least three atoms being part of at least two amino acid residues comprising the peptide sequence, whereby such at least three atoms and the metal ion form a ring structure comprising at least one ring, the at least one ring of the ring structure defining a template space;
• (e) screening the library of metallopeptides for binding to the target of interest;
• (f) selecting a metallopeptide exhibiting binding to the target of interest;
• (g) modeling a non-peptidic ring structure that is superimposable on the template space defined by at least one ring of the ring structure of the selected metallopeptide;
• and
• (h) forming a peptidomimetic by adding to the non-peptidic ring structure at least two elements independently comprising an amino acid residue, amino acid side chain moiety or derivative thereof, such at least two elements occupying a similar descriptor space as corresponding elements of the selected metallopeptide.