Human cytomegalovirus (HCMV) is a ubiquitous pathogen that presents a health risk to immunocompromised patients and neonates. The life cycle of the virus is dependent upon a self-processing serine protease (HCMV protease). The targeted inhibition of this protease appears to be a viable strategy for the disruption of viral replication. Proposed inhibitors have been designed through a knowledge of the natural cleavage site of HCMV protease and a knowledge of the binding pocket of the enzyme. ? ? A zinc-carbenoid mediated approach to the formation of potential inhibitors of this virus is described. Amino acid-derived beta-keto ester and beta-keto amides will be chain extended to their gamma-keto homologues. These gamma-keto esters and amides are presented as isosteric replacements (ketomethylene isosteres) for the scissile peptide bond. The zinc-mediated approach to the preparation of these molecules will allow the preparation of a wide variety of amino acid mimics through selection of appropriate amino acid starting materials and application of tandem reaction procedures. Diastereoselective incorporation of amino acid side chain mimics will be addressed through tandem chain extension-aldol, chain extension-homoenolate, and chain extension-oxidation protocols. ? ? The designs of two novel isosteric groups are proposed. These isosteres involve the inclusion of a tetrahydrofuran or beta-proline within the peptide backbone. These cyclic dipeptide mimics are fundamentally different than the ketomethylene isosteres described above and may be useful for the inhibition of a variety of protease targets. ? ?
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