Synergistic Anti-Zika Activity of Repurposed Statin and Clofibrate Combinations: Evidence from Oleic Acid-Mediated Metabolic Complementation
7 affiliations
- 1Department of Veterinary Pathology, College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, Gwangju 61186, Republic of Korea
- 2Animal Medical Institute, Chonnam National University, Gwangju 61186, Republic of Korea
- 3Department of Veterinary Pathology, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea
- 4Department of Food and Environmental Hygiene, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea
- 5Texas Biomedical Research Institute, San Antonio, TX 78227, USA
- 6Centro Nacional de Biotecnología (CNB-CSIC), Darwin 3, Campus Cantoblanco UAM, 28049 Madrid, Spain
- 7Department of Veterinary Zoonotic Diseases, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Republic of Korea
Abstract
Zika virus (ZIKV) substantially relies on host lipid metabolism, presenting a prime target for host-directed antivirals. To identify host-directed antiviral interventions while circumventing interferon-mediated transcriptomic masking, we curated a dual-virus (dengue and ZIKV) gene signature to query the Connectivity Map. Top lipid-lowering candidates were validated using a reporter virus (rZIKV-Venus) and an authentic wild-type (WT) ZIKV in Vero E6 cells—a model deliberately selected for its interferon deficiency to isolate pure metabolic responses. Dose–response screening of 67 prioritized compounds identified atorvastatin, rosuvastatin, and clofibrate as potent ZIKV inhibitors. Statin–clofibrate combinations exhibited strong synergy, with fractional inhibitory concentration index (FICI) values of 0.203 (atorvastatin–clofibrate) and 0.117 (rosuvastatin–clofibrate) for the 4:1 clofibrate-to-statin ratio and an optimized selectivity index. Mechanistically, exogenous oleic acid supplementation induced significant metabolic complementation, significantly restoring both host lipid droplet (LD) abundance and ZIKV replication readouts suppressed by the dual treatment. Relative LD intensity strongly correlated with viral intensity in both models (Pearson r = 0.951 and 0.956, respectively; both p < 0.0001). These findings demonstrate that concurrent pharmacological modulation of host lipid metabolism exerts synergistic anti-ZIKV effects, highlighting highly curated transcriptomic repurposing as a mechanistic prioritization strategy for host-directed antiviral discovery.
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BibTeX
@article{lee2026synergistic,
title = {{Synergistic Anti-Zika Activity of Repurposed Statin and Clofibrate Combinations: Evidence from Oleic Acid-Mediated Metabolic Complementation}},
author = {Chung-Do Lee and Sang-Ik Park and Gun Lee and Hyeon Jeong Moon and Jaewoo Choi and Jun Bong Lee and Luis Martinez-Sobrido and Fernando Almazán and Eun-Hye Ryu and Yeong-Bin Baek and Jun-Gyu Park},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219637},
url = {https://www.mdpi.com/1422-0067/27/21/9637},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Synergistic Anti-Zika Activity of Repurposed Statin and Clofibrate Combinations: Evidence from Oleic Acid-Mediated Metabolic Complementation
AU - Chung-Do Lee
AU - Sang-Ik Park
AU - Gun Lee
AU - Hyeon Jeong Moon
AU - Jaewoo Choi
AU - Jun Bong Lee
AU - Luis Martinez-Sobrido
AU - Fernando Almazán
AU - Eun-Hye Ryu
AU - Yeong-Bin Baek
AU - Jun-Gyu Park
PY - 2026
DA - 2026/10/28
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219637
UR - https://www.mdpi.com/1422-0067/27/21/9637
AB - Zika virus (ZIKV) substantially relies on host lipid metabolism, presenting a prime target for host-directed antivirals. To identify host-directed antiviral interventions while circumventing interferon-mediated transcriptomic masking, we curated a dual-virus (dengue and ZIKV) gene signature to query the Connectivity Map. Top lipid-lowering candidates were validated using a reporter virus (rZIKV-Venus) and an authentic wild-type (WT) ZIKV in Vero E6 cells—a model deliberately selected for its interferon deficiency to isolate pure metabolic responses. Dose–response screening of 67 prioritized compounds identified atorvastatin, rosuvastatin, and clofibrate as potent ZIKV inhibitors. Statin–clofibrate combinations exhibited strong synergy, with fractional inhibitory concentration index (FICI) values of 0.203 (atorvastatin–clofibrate) and 0.117 (rosuvastatin–clofibrate) for the 4:1 clofibrate-to-statin ratio and an optimized selectivity index. Mechanistically, exogenous oleic acid supplementation induced significant metabolic complementation, significantly restoring both host lipid droplet (LD) abundance and ZIKV replication readouts suppressed by the dual treatment. Relative LD intensity strongly correlated with viral intensity in both models (Pearson r = 0.951 and 0.956, respectively; both p < 0.0001). These findings demonstrate that concurrent pharmacological modulation of host lipid metabolism exerts synergistic anti-ZIKV effects, highlighting highly curated transcriptomic repurposing as a mechanistic prioritization strategy for host-directed antiviral discovery.
SN - 1422-0067
ER -