Inhibition of severe acute respiratory syndrome-associated coronavirus (SARSCoV) by calpain inhibitors and beta-D-N4-hydroxycytidine.
We evaluated two types of compounds for efficacy in inhibiting SARSCoV replication in vitro: calpain inhibitors (a class of cellular cysteine proteinases) and a number of nucleoside analogues. Cytopathic effect reduction assays visually determined with spectrophotometric verification by neutral red (NR) uptake assay were used to evaluate cytotoxicity and antiviral potency of the compounds. Significantly inhibitory compounds were then evaluated in virus yield reduction assays. Two calpain inhibitors, Val-Leu-CHO (calpain inhibitor VI) and Z-Val-Phe-Ala-CHO (calpain inhibitor III), were the most potent inhibitors of SARSCoV. By virus yield reduction assay, calpain inhibitor VI had a 90% effective concentration (EC90) of 3 microM and calpain inhibitor III had an EC90 of 15 microM. Beta-D-N4-hydroxycytidine was the most selective nucleoside analogue inhibitor with an EC90 of 6 microM by virus yield reduction assay. These compounds or analogues warrant further evaluation as potential therapies for treating SARS or could be used as lead compounds for discovery of more potent SARSCoV inhibitors.
Barnard
Dale L
DL
Institute for Antiviral Research, Utah State University, Logan, UT, USA. honery@cc.usu.edu
Hubbard
Valerie D
VD
Burton
Jared
J
Smee
Donald F
DF
Morrey
John D
JD
Otto
Michael J
MJ
Sidwell
Robert W
RW
D000818:Animals; D002522:Chlorocebus aethiops; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006023:Glycoproteins / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology; D045473:Severe acute respiratory syndrome-related coronavirus / Q000145:classification / Q000187:drug effects* / Q000502:physiology; D045169:Severe Acute Respiratory Syndrome / Q000821:virology*; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
D006023:Glycoproteins; D009705:Nucleosides; C039304:calpain inhibitors; D003562:Cytidine; C010737:N(4)-hydroxycytidine