Enzyme inhibitors form basis of new SARS drugs
appear to block the replication of the SARS virus - a finding that
could help speed up the research and development of drugs used to
treat the killer virus.
"We have been working on the problem of SARS since the epidemic started in 2003," said Chi-Huey Wong, director of the Scripps Research lab heading the study.
"This new class of inhibitors represents the most potent SARS virus protease inhibitors known today."
Researchers from Scripps Research, the Genomics Research Center, Academia Sinica, Taiwan; and the National Taiwan University, have been looking at a protease inhibitor of HIV also known as TL3, known to be a weak inhibitor of the SARS 3CLpro site.
During these experiments, they found that a group of catalysing agents used to help promote chemical reactions in the laboratory were actually more powerful in blocking the SARS protease than either the Lopinavir or any of the target compounds.
These organic compounds are called benzotriazole esters. The esters entered the SARS protease site, formed an intermediary compound, and then inactivated the SARS enzyme. The findings were confirmed using mass spectrometry analysis of the enzyme intermediary.
"These benzotriazole esters are relatively stable and act as suicide inhibitors," Wong said.
Wong said the findings provided better insight into the mode of action of the enzyme, which may lead to development of a drug against SARS.
The findings were made by using rapid drug discovery techniques developed in the Wong lab to screen large numbers of weak enzyme inhibitors, and then attaching additional compounds to look for stronger reactions.
Research Associate Chung-Yi Wu, a member of the Wong lab, is the paper's lead author. He said the finding was unexpected.
"We wanted to improve Liponavir activity," Wu said. "But we found this very surprising and serendipitous result."
A ring-shaped virus, known as a coronavirus, causes SARS. The SARS coronavirus is suspected of originating in animal populations before migrating to humans.
Hardest-hit were six Asian nations. By the time the epidemic had been controlled in 2003, the disease infected more than 8,000 people, causing 800 deaths. There is no current effective treatment or vaccine.
The study is to be published in the journal >Chemistry and Biology,/a> (Vol. 13, No. 3).
