The overall goal of the proposed research is to design, synthesize and evaluate new heterocyclic compounds with potential for the inhibition of HCMV infections. This will be a comprehensive approach involving interactions between the synthesis program, the in vitro biological evaluation program, the immunological program, the in vivo evaluation core component and the industrial collaborator. The primary rationale is to design and synthesize compounds that will be potent and specific inhibitors of HCMV infections. This specificity (selectivity) will be established by evaluating compounds against other viruses (e.g. HSV-I) and normal mammalian cells in addition to HCMV. These studies will provide feedback to the synthesis program and allow the synthetic efforts to remain focussed on those areas with a very high potential of providing compounds with inhibitory properties against HCMV infections. The detailed specific aims by which the above stated objectives will be accomplished are described in the specific sections for each of the laboratory research programs.
These aims can be summarized as follows: 1) to establish a Central Operations Component to facilitate the interactions and communication between the research programs the industrial collaborator and the NIAID staff; 2) (Laboratory Research Program I) to design and synthesize new heterocyclic compounds as potential agents against HCMV infections. The synthetic efforts will be guided to a certain extend by feedback from the biological components of the NCDDG; 3) (Laboratory Research Program II) to evaluate new heterocyclic compounds for activity against HCMV (plaque reduction and titer reduction), activity against other viruses (e.g. HSV I, HSV II, etc.), cytotoxicity (HFF and KB cells) and to perform in vitro metabolism studies and inhibition studies of certain target enzymes or biological processes; 4) (Laboratory Research Program III) to study the immunologic parameters of compounds deemed to be active HCMV agents by Laboratory Research Program II's criteria; 5) (In vivo Core Component) this laboratory will perform in vivo evaluations on a limited number of compounds, the selection being made by a consensus of the Principal Investigator, Program Leaders and the NIAID liaison; 6) (Industrial Collaboration) to involve the industrial collaborator in discussions and decisions on the appropriate studies that will be needed for the further development of agents that are at the in vivo evaluation stage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI031718-03
Application #
3547875
Study Section
Special Emphasis Panel (SRC (60))
Project Start
1991-08-01
Project End
1995-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Pharmacy
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Krosky, Paula M; Borysko, Katherine Z; Nassiri, M Reza et al. (2002) Phosphorylation of beta-D-ribosylbenzimidazoles is not required for activity against human cytomegalovirus. Antimicrob Agents Chemother 46:478-86
Evers, David L; Komazin, Gloria; Shin, Dongjin et al. (2002) Interactions among antiviral drugs acting late in the replication cycle of human cytomegalovirus. Antiviral Res 56:61-72
Zou, R; Kawashima, E; Freeman, G A et al. (2000) Design, synthesis, and antiviral evaluation of 2-deoxy-D-ribosides of substituted benzimidazoles as potential agents for human cytomegalovirus infections. Nucleosides Nucleotides Nucleic Acids 19:125-53
Gudmundsson, K S; Freeman, G A; Drach, J C et al. (2000) Synthesis of fluorosugar analogues of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole as antivirals with potentially increased glycosidic bond stability. J Med Chem 43:2473-8
Krosky, P M; Ptak, R G; Underwood, M R et al. (2000) Differences in DNA packaging genes and sensitivity to benzimidazole ribonucleosides between human cytomegalovirus strains AD169 and Towne. Antivir Chem Chemother 11:349-52
Gudmundsson, K S; Tidwell, J; Lippa, N et al. (2000) Synthesis and antiviral evaluation of halogenated beta-D- and -L-erythrofuranosylbenzimidazoles. J Med Chem 43:2464-72
Nassiri, M R; Gilloteaux, J; Taichman, R S et al. (1998) Ultrastructural aspects of cytomegalovirus-infected fibroblastic stromal cells of human bone marrow. Tissue Cell 30:398-406
Porcari, A R; Devivar, R V; Kucera, L S et al. (1998) Design, synthesis, and antiviral evaluations of 1-(substituted benzyl)-2-substituted-5,6-dichlorobenzimidazoles as nonnucleoside analogues of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole. J Med Chem 41:1252-62
Krosky, P M; Underwood, M R; Turk, S R et al. (1998) Resistance of human cytomegalovirus to benzimidazole ribonucleosides maps to two open reading frames: UL89 and UL56. J Virol 72:4721-8
Migawa, M T; Girardet, J L; Walker 2nd, J A et al. (1998) Design, synthesis, and antiviral activity of alpha-nucleosides: D- and L-isomers of lyxofuranosyl- and (5-deoxylyxofuranosyl)benzimidazoles. J Med Chem 41:1242-51

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