John Montgomery's legacy: carbocyclic adenosine analogues as SAH hydrolase inhibitors with broad-spectrum antiviral activity.
Ever since the S-adenosylhomocysteine (AdoHcy, SAH) hydrolase was recognized as a pharmacological target for antiviral agents (J. A. Montgomery et al., J. Med. Chem. 25:626-629, 1982), an increasing number of adenosine, acyclic adenosine, and carbocyclic adenosine analogues have been described as potent SAH hydrolase inhibitors endowed with broad-spectrum antiviral activity. The antiviral activity spectrum of the SAH hydrolase inhibitors include pox-, rhabdo-, filo-, arena-, paramyxo-, reo-, and retroviruses. Among the most potent SAH hydrolase inhibitors and antiviral agents rank carbocyclic 3-deazaadenosine (C-c3 Ado), neplanocin A, 3-deazaneplanocin A, the 5'-nor derivatives of carbocyclic adenosine (C-Ado, aristeromycin), and the 2-halo (i.e., 2-fluoro) and 6'-R-alkyl (i.e., 6'-R-methyl) derivatives of neplanocin A. These compounds are particularly active against poxviruses (i.e., vaccinia virus), and rhabdoviruses (i.e., vesicular stomatitis virus). The in vivo efficacy of C-c3 Ado and 3-deazaneplanocin A has been established in mouse models for vaccinia virus, vesicular stomatitis virus, and Ebola virus. SAH hydrolase inhibitors such as C-c3Ado and 3-deazaneplanocin A should in thefirst place be considered for therapeutic (or prophylactic) use against poxvirus infections, including smallpox, and hemorrhagic fever virus infections such as Ebola.
De Clercq
Erik
E
Rega Institute for Medical Research, Department of Microbiology and Immunology, K.U. Letven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. erik.declercq@rega.kuleuven.be
D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors*; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D049673:History, 20th Century; D049674:History, 21st Century; D006801:Humans; D051379:Mice; D014764:Viral Proteins / Q000037:antagonists & inhibitors*; D014777:Virus Diseases / Q000188:drug therapy* / Q000201:enzymology; D014780:Viruses / Q000201:enzymology*
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D014764:Viral Proteins; C048460:3-deazaneplanocin; D043383:Adenosylhomocysteinase; D000241:Adenosine