Antivirals at the mirror: the lack of stereospecificity of some viral and human enzymes offers novel opportunities in antiviral drug development.
The enantioselectivity of enzymes, namely the property of enzymes to recognise and metabolise only one of the two enantiomers of chiral molecules, is related to the chiral structure of the enzymes, reflecting the three-dimensional folding of the polypeptide backbone and the orientation of the amino acid side chains in the folded molecule. Because of the chirality of the amino acids (L), the chemistry of life should be highly sensitive to different enantiomers of chiral substrates. However, in a world consisting only of D-nucleosides and L-amino acids, an enzyme which lacks enantio-selectivity does not reduce its fitness, since there is no chance of molecular misunderstanding when no other choice is available. Thus, although enantioselectivity is theoretically essential for life we do not expect to be always present among the biochemical properties of enzymes. If this is the case for key enzymes involved in virus infection or cancer, how to exploit such lack of enantioselectivity for a novel approach to antiviral or anticancer chemotherapy? The present review will discuss the possible lack of enantioselectivity of enzymes and its relevance for the developing of novel drugs with the inverted optical configuration.
Focher
Federico
F
Istituto di Genetica Molecolare IGM-CNR, Consiglio Nazionale delle Ricerche, Via Abbiategrasso 207, I-27100 Pavia, Italy.
Spadari
Silvio
S
Maga
Giovanni
G
D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015316:Genetic Therapy; D006801:Humans; D009369:Neoplasms / Q000628:therapy; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013237:Stereoisomerism; D013936:Thymidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D014777:Virus Diseases / Q000628:therapy; D014780:Viruses / Q000187:drug effects* / Q000201:enzymology*
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009705:Nucleosides; D014764:Viral Proteins; D013936:Thymidine