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SARS coronavirus replication requires two consecutive cleavages of the viral replicase polyprotein at sites P1/SPN and P16. Recently, two peptidomimetic inhibitors, diketopiperazine-1 (DKP-1) and diketopiperazine-2 (DKP-2), were found to significantly inhibit this process. Both DKP-1 and DKP-2 consist of piperazine derivatives linked at the N-terminus with a phenylalanylalanine derivative and contain a tetrapeptide moiety at the C-terminus. We designed a series of novel acyclic peptidomimetics as mimetics of the tetrapeptide moiety at the C-terminus, aiming at the replacement of DKP-1 and DKP-2. In this paper, we report on the design and synthesis of a series of cyclic and acyclic peptidomimetics, and on their preliminary evaluation as inhibitors of SARS coronavirus main proteinase (M(pro)). Their inhibitory activity against SARS coronavirus

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