John Montgomery's legacy: carbocyclic adenosine analogues as SAH hydrolase inhibitors with broad-spectrum antiviral activity.

Abstract

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.

• Authors: Erik De Clercq
• Journal: Nucleosides, nucleotides & nucleic acids (Nucleosides Nucleotides Nucleic Acids) Vol. 24 Issue 10-12 Pg. 1395-415 ( 2005) ISSN: 1525-7770 [Print] United States
• PMID: 16438025 (Publication Type: Biography, Historical Article)

Chemical References

• Antiviral Agents
• Enzyme Inhibitors
• Viral Proteins
• 3-deazaneplanocin
• Adenosylhomocysteinase
• Adenosine

Topics

• Adenosine (analogs & derivatives, therapeutic use)
• Adenosylhomocysteinase (antagonists & inhibitors)
• Animals
• Antiviral Agents (therapeutic use)
• Enzyme Inhibitors (therapeutic use)
• History, 20th Century
• History, 21st Century
• Humans
• Mice
• Viral Proteins (antagonists & inhibitors)
• Virus Diseases (drug therapy, enzymology)
• Viruses (enzymology)