TY - JOUR
T1 - Anthracene-based inhibitors of dengue virus NS2B-NS3 protease
AU - Tomlinson, Suzanne M.
AU - Watowich, Stanley J.
N1 - Funding Information:
This research was supported in part by NIH/NIAID AI066160 (SJW), the Welch Foundation H-1642 (SJW), a training fellowship to SMT from the Computational and Structural Biology in Biodefense Training Program of the W.M. Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia (NIAID Grant No. 1 T32 AI065396-01 ), and a National Library of Medicine training fellowship in Computational Biology and Biomedical Informatics to the Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia (NLM Grant No. T15 LM007093 ).
PY - 2011/2
Y1 - 2011/2
N2 - Dengue virus (DENV) is a mosquito-borne flavivirus that has strained global healthcare systems throughout tropical and subtropical regions of the world. In addition to plaguing developing nations, it has re-emerged in several developed countries with recent outbreaks in the USA (CDC, 2010), Australia (Hanna et al., 2009), Taiwan (Kuan et al., 2010) and France (La Ruche et al., 2010). DENV infection can cause significant disease, including dengue fever, dengue hemorrhagic fever, dengue shock syndrome, and death. There are no approved vaccines or antiviral therapies to prevent or treat dengue-related illnesses. However, the viral NS2B-NS3 protease complex provides a strategic target for antiviral drug development since NS3 protease activity is required for virus replication. Recently, we reported two compounds with inhibitory activity against the DENV protease in vitro and antiviral activity against dengue 2 (DEN2V) in cell culture (Tomlinson et al., 2009a). Analogs of one of the lead compounds were purchased, tested in protease inhibition assays, and the data evaluated with detailed kinetic analyses. A structure activity relationship (SAR) identified key atomic determinants (i.e. functional groups) important for inhibitory activity. Four " second series" analogs were selected and tested to validate our SAR and structural models. Here, we report improvements to inhibitory activity ranging between ∼2- and 60-fold, resulting in selective low micromolar dengue protease inhibitors.
AB - Dengue virus (DENV) is a mosquito-borne flavivirus that has strained global healthcare systems throughout tropical and subtropical regions of the world. In addition to plaguing developing nations, it has re-emerged in several developed countries with recent outbreaks in the USA (CDC, 2010), Australia (Hanna et al., 2009), Taiwan (Kuan et al., 2010) and France (La Ruche et al., 2010). DENV infection can cause significant disease, including dengue fever, dengue hemorrhagic fever, dengue shock syndrome, and death. There are no approved vaccines or antiviral therapies to prevent or treat dengue-related illnesses. However, the viral NS2B-NS3 protease complex provides a strategic target for antiviral drug development since NS3 protease activity is required for virus replication. Recently, we reported two compounds with inhibitory activity against the DENV protease in vitro and antiviral activity against dengue 2 (DEN2V) in cell culture (Tomlinson et al., 2009a). Analogs of one of the lead compounds were purchased, tested in protease inhibition assays, and the data evaluated with detailed kinetic analyses. A structure activity relationship (SAR) identified key atomic determinants (i.e. functional groups) important for inhibitory activity. Four " second series" analogs were selected and tested to validate our SAR and structural models. Here, we report improvements to inhibitory activity ranging between ∼2- and 60-fold, resulting in selective low micromolar dengue protease inhibitors.
KW - Dengue virus
KW - Flavivirus
KW - NS2B-NS3
KW - Protease
KW - Small-molecule inhibitor
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U2 - 10.1016/j.antiviral.2010.12.006
DO - 10.1016/j.antiviral.2010.12.006
M3 - Article
C2 - 21185332
AN - SCOPUS:78751620005
SN - 0166-3542
VL - 89
SP - 127
EP - 135
JO - Antiviral research
JF - Antiviral research
IS - 2
ER -