We take molecular approaches to herpesviruses, especially to understand processes that distinguish viral functions from cellular functions, which can be exploited to permit antiviral therapy. The foci are 1) post-transcriptional regulation of gene expression, 2) functional dissection of replication proteins, 3) analysis of virus latency, a fascinating and clinically important topic, 4) antiviral drug targets, drug mechanisms, and drug resistance.
Novel post-transcriptional regulatory mechanisms: We are studying post-transcriptional regulation of herpes simplex virus genes, including microRNAs, regulated polyadenylation, ribosomal frameshifting, internal ribosome entry sites, and translational regulation.
Herpesvirus DNA replication proteins: antiviral drug targets and prototypes for human replication proteins. We are currently focusing on determining the 3-D structures of these proteins (with the Hogle lab) and exploring their interactions with each other and nucleic acids via biochemical, mutational, and biophysical approaches, including (with the Golan and van Oijen labs) single molecule methods. These studies should permit detailed understanding of these complicated proteins and the process of viral DNA replication, and rational drug design.
Latency and pathogenesis: We use virus mutants, PCR-based methods, and microarray technologies to explore viral and neuronal gene function and regulation (e.g. how viral gene expression is repressed by microRNAs) during latency and mechanisms by which drug resistant mutants retain pathogenicity. Drugs: Aside from our studies of herpesvirus DNA replication proteins. we are exploiting for drug discovery the human cytomegalovirus protein kinase that phosphorylates ganciclovir, investigating how it promotes nuclear egress of nucleocapsids, and are finding new drug targets, especially by screening chemical libraries and studies of drug-resistant mutants.
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References:
Krosky PM, Baek M-C, Coen DM. The human cytomegalovirus UL97 protein kinase, an antiviral drug target, is required at the stage of nuclear egress. J Virol 2003:77, 905-914.
Kramer MF, Cook WJ, Roth FP, Zhu J, Holman H, Knipe DM, Coen DM. Latent herpes simplex virus infection of sensory neurons alters neuronal gene expression. J Virol 2003; 77:9533-9541.
Appleton BA, Loregian A, Filman DJ, Coen DM, Hogle JM. The cytomegalovirus DNA polymerase subunit UL44 forms a C-clamp shaped dimer. Mol Cell 2004; 15; 233-244.
Griffiths A, Coen DM. A novel internal ribosome entry site in the herpes simplex virus thymidine kinase gene. Proc Natl Acad Sci USA; 2005; 102:9667-9772.
Loregian A, Coen DM. Selective anti-cytomegalovirus compounds discovered by screening for inhibitors of subunit interactions of the viral polymerase. Chem Biol 2006; 13:191-200.
Cui C, Griffiths A, Li G, Silva LM, Kramer MF, Gaasterland T, Wang X-J, Coen DM. Prediction and identification of herpes simplex virus 1-encoded microRNAs. J Virol 2006; 80:5499-5508.
Hume AJ, Finkel JS, Kamil JP, Coen DM, Culbertson MR, Kalejta, RF. Phosphorylation of etinoblastoma protein viral protein with cyclin-dependent kinase function. Science 2008; 320:797-799.
Lin Umbach J, Kramer MF, Jurak I, Karnowski HW, Coen DM, Cullen BR. MicroRNAs expressed by herpes simplex virus 1 during latent infection regulate viral mRNAs. Nature; 2008; in press.
Komazin-Meredith G, Mirchev, R, Golan, DE, van Oijen AM, Coen DM. Hopping of a processivity factor on DNA revealed by single molecule assays of diffusion. Proc Natl Acad Sci USA; accepted for publication.
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