Targeting cysteine residues of biomolecules: new approaches for the design of antiviral and anticancer drugs.
Modification of cysteine (Cys) residues in proteins, due to (i) the participation of the thiol moiety of this amino acid in oxido-reductions reactions; (ii) its ability to strongly coordinate transition metal ions; or (iii) its nucleophilic nature and facile reaction with electrophiles, may be of critical importance for the design of novel types of pharmacological agents. Application of such procedures, recently led to the design of novel antivirals, mainly based on the reaction of zinc finger proteins with disulfides and related derivatives. This approach was particularly successful for developing novel anti-HIV and anti-HPV agents. Several new anticancer therapeutic approaches, mainly targeting tubulin, Ras and fanesyl transferase among others, have also been reported. Miscellaneous other agents/procedures which found less applications for the moment, and which are based on Cys modification reactions, are reviewed. This unique amino acid offers very interesting possibilities to develop particularly useful pharmacological agents, which generally possess a completely different mechanism of action as compared to classical agents in clinical use, avoiding their major problems such as multidrug-resistance of antivirals or antitumor agents or high toxicity associated with classical such chemotherapeutic agents.
Scozzafava
Andrea
A
Università degli Studi, Polo Scientifico, Laboratorio di Chimica Bioinorganica, Sesto Fiorentino, Florence, Italy.
Casini
Angela
A
Supuran
Claudiu T
CT
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D011506:Proteins; D013438:Sulfhydryl Compounds; D003545:Cysteine