NS5 synthesizes minus strand genome

Stable Identifier
R-HSA-9922955
Type
Reaction [uncertain]
Species
Homo sapiens
Related Species
Dengue virus type 2
Compartment
cytosol
ReviewStatus
5/5
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NS5 synthesizes minus strand genome
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RNA-dependent RNA polymerase (RdRp) domain of NS5 subunit of the DENV Replication Complex (RC) synthesizes a DENV nascent -ssRNA genome replicate from the +ssRNA template, using NTPs. The RdRp domain is involved in RNA replication in both the de novo initiation and the elongation steps (reviewed in van den Elsen et al., 2021). For instance, recombinant DENV-1 (strain S275/90) NS5 protein expressed in E. coli exhibits RNA-dependent RNA polymerase activity in vitro, consistent with its role in RNA synthesis (Tan et al., 1996). NS5 recognizes the stem–loop A (SLA) in the 5′ untranslated region (UTR) of viral RNA; this recognition is a key aspect of replication (reviewed in Choi et al., 2021), and in vitro binding to 5'SLA has been demonstrated for DENV-2 (strain 3295) NS5 protein expressed in E. coli (Wang et al., 2022). The exact mechanism of replication is unclear (reviewed in van den Elsen et al., 2021).

Several FDA-approved small molecules inhibit NS5's RNA-dependent RNA-polymerase (RdRp) activity. Galidesivir (BCX4430) is an adenosine nucleoside analog that has successfully completed phase I clinical trials, involving SARS-CoV-2 and Marburg virus infections; it inhibits NS5 in vitro and reduces Dengue and Zika viral load (Deshpande et al., 2023; Julander et al., 2018). Entrectinib is an approved cancer therapeutic; it inhibits NS5 polymerase activity in in vitro biochemical assays (Yi et al., 2020). Sofosbuvir is approved for Hepatitis C virus (HCV) treatment; it acts as a chain terminator of DENV RNA replication (Xu et al., 2017; Sacramento et al., 2018; reviewed in Picarazzi et al., 2020).
Literature References
PubMed ID Title Journal Year
27838352 Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model

Julander, JG, Siddharthan, V, Evans, J, Taylor, R, Tolbert, K, Apuli, C, Stewart, J, Collins, P, Gebre, M, Neilson, S, Van Wettere, A, Lee, YM, Sheridan, WP, Morrey, JD, Babu, YS

Antiviral Res 2017
8607261 Recombinant dengue type 1 virus NS5 protein expressed in Escherichia coli exhibits RNA-dependent RNA polymerase activity

Tan, BH, Fu, J, Sugrue, RJ, Yap, EH, Chan, YC, Tan, YH

Virology 1996
28740124 Evaluation of Sofosbuvir (β-D-2'-deoxy-2'-α-fluoro-2'-β-C-methyluridine) as an inhibitor of Dengue virus replication<sup/>

Xu, HT, Colby-Germinario, SP, Hassounah, SA, Fogarty, C, Osman, N, Palanisamy, N, Han, Y, Oliveira, M, Quan, Y, Wainberg, MA

Sci Rep 2017
34064113 Molecular Insights into the Flavivirus Replication Complex

van den Elsen, K, Quek, JP, Luo, D

Viruses 2021
28098253 The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication

Sacramento, CQ, de Melo, GR, de Freitas, CS, Rocha, N, Hoelz, LV, Miranda, M, Fintelman-Rodrigues, N, Marttorelli, A, Ferreira, AC, Barbosa-Lima, G, Abrantes, JL, Vieira, YR, Bastos, MM, de Mello Volotão, E, Nunes, EP, Tschoeke, DA, Leomil, L, Loiola, EC, Trindade, P, Rehen, SK, Bozza, FA, Bozza, PT, Boechat, N, Thompson, FL, de Filippis, AM, Brüning, K, Souza, TM

Sci Rep 2017
34759006 A conserved arginine in NS5 binds genomic 3' stem-loop RNA for primer-independent initiation of flavivirus RNA replication

Wang, S, Chan, KWK, Tan, MJA, Flory, C, Luo, D, Lescar, J, Forwood, JK, Vasudevan, SG

RNA 2022
32670253 Identification of a Broad-Spectrum Viral Inhibitor Targeting a Novel Allosteric Site in the RNA-Dependent RNA Polymerases of Dengue Virus and Norovirus

Yi, D, Li, Q, Pang, L, Wang, Y, Zhang, Y, Duan, Z, Liang, C, Cen, S

Front Microbiol 2020
34207869 The Role of the Stem-Loop A RNA Promoter in Flavivirus Replication

Choi, KH

Viruses 2021
33287144 Targeting the RdRp of Emerging RNA Viruses: The Structure-Based Drug Design Challenge

Picarazzi, F, Vicenti, I, Saladini, F, Zazzi, M, Mori, M

Molecules 2020
Participants
Input
Output
Participates
as an event of
Event Information
Go Biological Process
viral RNA genome replication (0039694)
Catalyst Activity

RNA-directed RNA polymerase activity of DENV circular genomic +ssRNA:RC [endoplasmic reticulum membrane]

Physical Entity
DENV circular genomic +ssRNA:RC [endoplasmic reticulum membrane] (Dengue virus type 2)
Activity
RNA-directed RNA polymerase activity (GO:0003968)
This event is regulated
Negatively by
Regulator
DENV polymerase inhibitors [cytosol]
Disease
Name Identifier Synonyms
dengue disease DOID:12205 breakbone fever, Dengue Fever, classic dengue
Cross References
RHEA
Mondo
Authored
Stephan, R  (2024-09-27)
Reviewed
Mansur, DS  (2025-09-18)
Roque Ascenção, F  (2025-10-29)
Roque Ascenção, F  (2026-03-03)
Created
Stephan, R  (2024-09-28)
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