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Sweeney NL, Hanson AM, Mukherjee S, et al. Benzothiazole and Pyrrolone Flavivirus Inhibitors Targeting the Viral Helicase. ACS Infect Dis. 2015;1(3):140-148doi: 10.1021/id5000458.
Sweeney, N. L., Hanson, A. M., Mukherjee, S., Ndjomou, J., Geiss, B. J., Steel, J. J., Frankowski, K. J., Li, K., Schoenen, F. J., & Frick, D. N. (2015). Benzothiazole and Pyrrolone Flavivirus Inhibitors Targeting the Viral Helicase. ACS infectious diseases, 1(3), 140-148. https://doi.org/10.1021/id5000458
Sweeney, Noreena L, et al. "Benzothiazole and Pyrrolone Flavivirus Inhibitors Targeting the Viral Helicase." ACS infectious diseases vol. 1,3 (2015): 140-148. doi: https://doi.org/10.1021/id5000458
Sweeney NL, Hanson AM, Mukherjee S, Ndjomou J, Geiss BJ, Steel JJ, Frankowski KJ, Li K, Schoenen FJ, Frick DN. Benzothiazole and Pyrrolone Flavivirus Inhibitors Targeting the Viral Helicase. ACS Infect Dis. 2015 Mar 13;1(3):140-148. doi: 10.1021/id5000458. PMID: 26029739; PMCID: PMC4444071.
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ACS Infect Dis. 2015 Mar 13;1(3):140-148. doi: 10.1021/id5000458.

Benzothiazole and Pyrrolone Flavivirus Inhibitors Targeting the Viral Helicase.

ACS infectious diseases

Noreena L Sweeney, Alicia M Hanson, Sourav Mukherjee, Jean Ndjomou, Brian J Geiss, J Jordan Steel, Kevin J Frankowski, Kelin Li, Frank J Schoenen, David N Frick

Affiliations

  1. Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 North Cramer Street, Milwaukee, Wisconsin 53211, United States.
  2. Department of Microbiology, Immunology, and Pathology, 1682 Campus Delivery, Colorado State University, Fort Collins, Colorado 80523, United States.
  3. Specialized Chemistry Center, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, United States.

PMID: 26029739 PMCID: PMC4444071 DOI: 10.1021/id5000458

Abstract

The flavivirus nonstructural protein 3 (NS3) is a protease and helicase, and on the basis of its similarity to its homologue encoded by the hepatitis C virus (HCV), the flavivirus NS3 might be a promising drug target. Few flavivirus helicase inhibitors have been reported, in part, because few specific inhibitors have been identified when nucleic acid unwinding assays have been used to screen for helicase inhibitors. To explore the possibility that compounds inhibiting NS3-catalyzed ATP hydrolysis might function as antivirals even if they do not inhibit RNA unwinding in vitro, we designed a robust dengue virus (DENV) NS3 ATPase assay suitable for high-throughput screening. Members of two classes of inhibitory compounds were further tested in DENV helicase-catalyzed RNA unwinding assays, assays monitoring HCV helicase action, subgenomic DENV replicon assays, and cell viability assays and for their ability to inhibit West Nile virus (Kunjin subtype) replication in cells. The first class contained analogues of NIH molecular probe ML283, a benzothiazole oligomer derived from the dye primuline, and they also inhibited HCV helicase and DENV NS3-catalyzed RNA unwinding. The most intriguing ML283 analogue inhibited DENV NS3 with an IC

Keywords: ATPase; Dengue fever; West Nile virus; direct acting antiviral; motor protein; nonstructural protein 3; positive sense single-stranded RNA ((+)ssRNA) virus; yellow fever virus

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