Cytomegalovirus (CMV) infection is common in humans, with seroprevalence rates reaching as high as 90% by adulthood. Although infection is usually asymptomatic in the normal host, CMV causes serious morbidity and mortality in immunocompromised cohorts, including transplant recipients and patients infected with HIV. CMV retinitis is a serious complication in patients with AIDS and profound immunosuppression. In addition, congenital CMV is the leading infectious cause of mental retardation and deafness in the United States. Current CMV therapies are effective in suppressing virus replication, but result in serious side effects, and the emergence of resistant viruses. Development of new compounds could significantly reduce morbidity and mortality from this pathogen. The overall goal of this application is to investigate the anti-CMV activities of artemisinins. Several artemisinin derivatives are widely used in malaria therapy. These compounds are orally available and have a good safety profile. The proposed investigation can be accomplished by our development of anti-viral assays and the availability of newly-synthesized artemisinin derivatives at Johns Hopkins University. We reported recently that dimeric artemisinins are dramatically more effective than the monomeric forms in inhibiting CMV replication in human fibroblasts. We have also shown that inhibition of CMV replication occurs at a very early stage of virus replication. The anti-CMV mechanism of artemisinins may be different than CMV inhibition by currently available compounds. We propose to identify the most potent anti-CMV artemisinin derivative, to evaluate whether combination with approved anti-CMV drugs is additive, and to elucidate mechanisms by which artemisinins inhibit CMV replication. This application is feasible and novel because we have acquired the experience and tools necessary for performing all experiments. For the first time we will use high throughput proteomics to identify the intracellular targets of artemisinins. The information derived from this application will have important impact on CMV therapy. It may lead to new concepts in CMV therapeutics by using a combination of compounds with direct anti-viral target and compounds which target a cellular protein that is important for CMV replication.

Public Health Relevance

Infection with Human Cytomegalovirus (CMV) is endemic, and associated with severe morbidity and mortality in congenitally-infected newborns and immunocompromised hosts. Treatment options for CMV infection are limited, and it is important to develop new therapeutic strategies against CMV. The overall aim of this proposal is to determine the activities and potential mechanisms of artemisinins as anti-CMV drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI093701-04
Application #
8603834
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Dempsey, Walla L
Project Start
2011-02-15
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
4
Fiscal Year
2014
Total Cost
$369,000
Indirect Cost
$144,000
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Cai, Hongyi; Kapoor, Arun; He, Ran et al. (2014) In vitro combination of anti-cytomegalovirus compounds acting through different targets: role of the slope parameter and insights into mechanisms of Action. Antimicrob Agents Chemother 58:986-94
Roy, S; Arav-Boger, R (2014) New cell-signaling pathways for controlling cytomegalovirus replication. Am J Transplant 14:1249-58
He, Ran; Forman, Michael; Mott, Bryan T et al. (2013) Unique and highly selective anticytomegalovirus activities of artemisinin-derived dimer diphenyl phosphate stem from combination of dimer unit and a diphenyl phosphate moiety. Antimicrob Agents Chemother 57:4208-14
Kapoor, Arun; He, Ran; Venkatadri, Rajkumar et al. (2013) Wnt modulating agents inhibit human cytomegalovirus replication. Antimicrob Agents Chemother 57:2761-7
Persaud, Deborah; Gay, Hannah; Ziemniak, Carrie et al. (2013) Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med 369:1828-35
He, Ran; Park, Kyoungsook; Cai, Hongyi et al. (2012) Artemisinin-derived dimer diphenyl phosphate is an irreversible inhibitor of human cytomegalovirus replication. Antimicrob Agents Chemother 56:3508-15
He, Ran; Mott, Bryan T; Rosenthal, Andrew S et al. (2011) An artemisinin-derived dimer has highly potent anti-cytomegalovirus (CMV) and anti-cancer activities. PLoS One 6:e24334