TY - JOUR
T1 - Cytomegalovirus UL97 mutations in the era of ganciclovir and maribavir
AU - Chou, Sunwen
PY - 2008/7
Y1 - 2008/7
N2 - Mutations in the human CMV UL97 kinase gene are a major mechanism of viral resistance to two anti-CMV drugs, ganciclovir (GCV) and maribavir (MBV). GCV, the most widely used and established therapy for CMV, is a substrate for the UL97 kinase. Well-characterised GCV-resistance mutations at UL97 codons 460, 520 and 590-607 impair the phosphorylation of GCV that is necessary for its antiviral activity, presumably by altering substrate recognition. In contrast, MBV is an inhibitor of the UL97 kinase and is the first new CMV therapy to reach later stage clinical trials in many years. No MBV-resistant CMV isolates have yet been detected in clinical trials, but after culture propagation under drug, UL97 mutations that confer moderate to high-level MBV resistance have been identified at codons 353, 397, 409 and 411. These mutations are located upstream of the GCV-resistance mutations and are close to the ATP-binding and catalytic domains common to all kinases, consistent with MBV acting as a small molecule ATP-competitive kinase inhibitor. So far, no UL97 mutations are known to confer resistance to both GCV and MBV.
AB - Mutations in the human CMV UL97 kinase gene are a major mechanism of viral resistance to two anti-CMV drugs, ganciclovir (GCV) and maribavir (MBV). GCV, the most widely used and established therapy for CMV, is a substrate for the UL97 kinase. Well-characterised GCV-resistance mutations at UL97 codons 460, 520 and 590-607 impair the phosphorylation of GCV that is necessary for its antiviral activity, presumably by altering substrate recognition. In contrast, MBV is an inhibitor of the UL97 kinase and is the first new CMV therapy to reach later stage clinical trials in many years. No MBV-resistant CMV isolates have yet been detected in clinical trials, but after culture propagation under drug, UL97 mutations that confer moderate to high-level MBV resistance have been identified at codons 353, 397, 409 and 411. These mutations are located upstream of the GCV-resistance mutations and are close to the ATP-binding and catalytic domains common to all kinases, consistent with MBV acting as a small molecule ATP-competitive kinase inhibitor. So far, no UL97 mutations are known to confer resistance to both GCV and MBV.
UR - http://www.scopus.com/inward/record.url?scp=47649088674&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=47649088674&partnerID=8YFLogxK
U2 - 10.1002/rmv.574
DO - 10.1002/rmv.574
M3 - Review article
C2 - 18383425
AN - SCOPUS:47649088674
SN - 1052-9276
VL - 18
SP - 233
EP - 246
JO - Reviews in Medical Virology
JF - Reviews in Medical Virology
IS - 4
ER -