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Abstract: MAPKAPK5 has been proposed to play a role in regulation of matrix metalloprotease expression and so to be a potential target for intervention in rheumatoid arthritis. We present here the identification of a series of compounds against this target which are effective in both biochemical and cell assays. The expansion of the series is described, along with early SAR and pharmacokinetics for some representative compounds. [Copyright &y& Elsevier]

Inhibition of CDK2/CA (cyclin-dependent kinase 2/cyclin A complex) activity through blocking of the substrate recognition site in the cyclin A subunit has been demonstrated to be an effective method for inducing apoptosis in tumor cells. We have used the cyclin binding motif (CBM) present in the tumor suppressor proteins p21WAF1 and p27KIP1 as a template to optimize the minimal sequence necessary for CDK2/CA inhibition. A series of peptides were prepared, containing nonnatural amino acids, which possess nano- to micromolar CDK2-inhibitory activity. Here we present X-ray structures of the protein complex CDK2/CA, together with the cyclin groove-bound peptides H-Ala-Ala-Abu-Arg-Ser-Leu-Ile-(p-F-Phe)-NH2 (peptide 1), H-Arg-Arg-Leu-Ile-Phe-NH2 (peptide 2), Ac-Arg-Arg-Leu-Asn-(m-Cl-Phe)-NH2 (peptide 3), H-Arg-Arg-Leu-Asn-(p-F-Phe)-NH2 (peptide 4), and H-Cit-Cit-Leu-Ile-(p-F-Phe)-NH2 (peptide 5). Some of the peptide complexes presented here were obtained through the novel technique of ligand exchange within protein crystals. This method may find general application for obtaining complex structures of proteins with surface-bound ligands. [Copyright &y& Elsevier]

Describes a novel route for the synthesis of cyclic peptides constrained by an aliphatic bridge between two C[sup alpha] sites, using a triply orthogonal protecting group strategy. Importance of the design and synthesis of conformationally constrained peptides and peptidomimetics in biological and medicinal chemistry; Synthesis of bis-amino acid; Contents of secondary structure for control peptide 14.