Homocysteine potentiates the antiviral and cytostatic activity of those nucleoside analogues that are targeted at S-adenosylhomocysteine hydrolase.
Various adenosine analogues, i.e. (S)-9-(2,3-dihydroxypropyl)adenine, (RS)-3-adenin-9-yl-2-hydroxypropanoic acid, carbocyclic 3-deazaadenosine and neplanocin A, which have been previously recognized as specific inhibitors of S-adenosyl-L-homocysteine (SAH) hydrolase, gained a marked increase in their cytostatic activity (against tumor cells) and antiviral activity (against vaccinia and vesicular stomatitis virus) in the presence of L-homocysteine (10(-3) M). Homocysteine did not increase the cytostatic or antiviral activity of those compounds (i.e. tubercidin, ribavirin, acyclovir or vidarabine) that do not achieve their biological activity via SAH hydrolase inhibition. The increased antiviral activity following addition of homocysteine was observed only with those viruses (i.e. vaccinia and vesicular stomatitis virus) that belong to the activity spectrum of SAH hydrolase inhibitors [Biochem Pharmacol 36: 2567-2575, 1987], and only in those cells in which the SAH hydrolase inhibitors are normally active. The enhancing effect of homocysteine on the cytostatic and antiviral activity of the SAH hydrolase inhibitors could not be attributed to a non-specific increase in the cytotoxicity of the compounds, as their effects on host cell macromolecule (DNA, RNA, protein) synthesis was not markedly altered in the presence of homocysteine. Most likely, homocysteine exerted its potentiating effect on the activity of the SAH hydrolase inhibitors through an increase in the intracellular levels of SAH, which is known to act as a product inhibitor of S-adenosyl-L-methionine (SAM)-dependent transmethylation reactions.
De Clercq
E
E
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Cools
M
M
Balzarini
J
J
D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D043383:Adenosylhomocysteinase; D000998:Antiviral Agents / Q000008:administration & dosage; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004357:Drug Synergism; D006710:Homocysteine / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D009363:Neoplasm Proteins / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000998:Antiviral Agents; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D006710:Homocysteine; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine