Cholesterol-Lowering Drugs As Potential Antivirals: A Repurposing Approach Against Flavivirus Infections

Overview

Journal Viruses

Publisher MDPI

Specialty Microbiology

Date 2023 Jul 29

PMID 37515153

Authors

Juan Fidel Osuna-Ramos

Carlos Noe Farfan-Morales

Carlos Daniel Cordero-Rivera

Luis Adrian De Jesus-Gonzalez

Jose Manuel Reyes-Ruiz

Arianna M Hurtado-Monzon

Selvin Noe Palacios-Rapalo

Ricardo Jimenez-Camacho

Marco Antonio Meraz-Rios

Rosa Maria Del Angel

Affiliations

Soon will be listed here.

Abstract

Flaviviruses, including Dengue (DENV), Zika (ZIKV), and Yellow Fever (YFV) viruses, represent a significant global health burden. The development of effective antiviral therapies against these viruses is crucial to mitigate their impact. This study investigated the antiviral potential of the cholesterol-lowering drugs atorvastatin and ezetimibe in monotherapy and combination against DENV, ZIKV, and YFV. In vitro results demonstrated a dose-dependent reduction in the percentage of infected cells for both drugs. The combination of atorvastatin and ezetimibe showed a synergistic effect against DENV 2, an additive effect against DENV 4 and ZIKV, and an antagonistic effect against YFV. In AG129 mice infected with DENV 2, monotherapy with atorvastatin or ezetimibe significantly reduced clinical signs and increased survival. However, the combination of both drugs did not significantly affect survival. This study provides valuable insights into the potential of atorvastatin and ezetimibe as antiviral agents against flaviviruses and highlights the need for further investigations into their combined therapeutic effects.

Citing Articles

A Comprehensive Review of the Development and Therapeutic Use of Antivirals in Flavivirus Infection.

Tripathi A, Chauhan S, Khasa R Viruses. 2025; 17(1).

PMID: 39861863 PMC: 11769230. DOI: 10.3390/v17010074.

The importance of paying attention to the role of lipid-lowering drugs in controlling dengue virus infection.

Allela O, Hashemi M, Heidari S, Kareem R, Sameer H, Adil M Virol J. 2024; 21(1):324.

PMID: 39702248 PMC: 11660873. DOI: 10.1186/s12985-024-02608-3.

The Low-Density Lipoprotein Receptor-Related Protein-1 Is Essential for Dengue Virus Infection.

Huerta V, Martin A, Sarria M, Guirola O, Yero A, Ramos Y Viruses. 2024; 16(11).

PMID: 39599807 PMC: 11599027. DOI: 10.3390/v16111692.

Integrating enzyme-nanoparticles bring new prospects for the diagnosis and treatment of immune dysregulation in periodontitis.

Zhang Q, Wang Z, Shen S, Wang J, Cao J, Deng Y Front Cell Infect Microbiol. 2024; 14:1494651.

PMID: 39554809 PMC: 11564189. DOI: 10.3389/fcimb.2024.1494651.

Orthoflaviviral Inhibitors in Clinical Trials, Preclinical In Vivo Efficacy Targeting NS2B-NS3 and Cellular Antiviral Activity via Competitive Protease Inhibition.

Cavina L, Bouma M, Girones D, Feiters M Molecules. 2024; 29(17).

PMID: 39274895 PMC: 11396989. DOI: 10.3390/molecules29174047.

References

Bajimaya S, Frankl T, Hayashi T, Takimoto T . Cholesterol is required for stability and infectivity of influenza A and respiratory syncytial viruses. Virology. 2017; 510:234-241. PMC: 5571833. DOI: 10.1016/j.virol.2017.07.024. View

Bryan-Marrugo O, Arellanos-Soto D, Rojas-Martinez A, Barrera-Saldana H, Ramos-Jimenez J, Vidaltamayo R . The anti‑dengue virus properties of statins may be associated with alterations in the cellular antiviral profile expression. Mol Med Rep. 2016; 14(3):2155-63. DOI: 10.3892/mmr.2016.5519. View

Pierson T, Diamond M . The continued threat of emerging flaviviruses. Nat Microbiol. 2020; 5(6):796-812. PMC: 7696730. DOI: 10.1038/s41564-020-0714-0. View

Osuna-Ramos J, Reyes-Ruiz J, Del Angel R . The Role of Host Cholesterol During Flavivirus Infection. Front Cell Infect Microbiol. 2018; 8:388. PMC: 6224431. DOI: 10.3389/fcimb.2018.00388. View

Ge L, Wang J, Qi W, Miao H, Cao J, Qu Y . The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1. Cell Metab. 2008; 7(6):508-19. DOI: 10.1016/j.cmet.2008.04.001. View

Espano E, Nam J, Song E, Song D, Lee C, Kim J . Lipophilic statins inhibit Zika virus production in Vero cells. Sci Rep. 2019; 9(1):11461. PMC: 6685969. DOI: 10.1038/s41598-019-47956-1. View

Farfan-Morales C, Cordero-Rivera C, Reyes-Ruiz J, Hurtado-Monzon A, Osuna-Ramos J, Gonzalez-Gonzalez A . Anti-flavivirus Properties of Lipid-Lowering Drugs. Front Physiol. 2021; 12:749770. PMC: 8529048. DOI: 10.3389/fphys.2021.749770. View

Lucifora J, Esser K, Protzer U . Ezetimibe blocks hepatitis B virus infection after virus uptake into hepatocytes. Antiviral Res. 2012; 97(2):195-7. DOI: 10.1016/j.antiviral.2012.12.008. View

Shrivastava S, Trivedi J, Mitra D . Gene expression profiling reveals Nef induced deregulation of lipid metabolism in HIV-1 infected T cells. Biochem Biophys Res Commun. 2016; 472(1):169-74. DOI: 10.1016/j.bbrc.2016.02.089. View

10.

Sainz Jr B, Barretto N, Martin D, Hiraga N, Imamura M, Hussain S . Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor. Nat Med. 2012; 18(2):281-5. PMC: 3530957. DOI: 10.1038/nm.2581. View

11.

Trivedi J, Mohan M, Byrareddy S . Drug Repurposing Approaches to Combating Viral Infections. J Clin Med. 2020; 9(11). PMC: 7700377. DOI: 10.3390/jcm9113777. View

12.

Chang T, Chang C . Ezetimibe blocks internalization of the NPC1L1/cholesterol complex. Cell Metab. 2008; 7(6):469-71. DOI: 10.1016/j.cmet.2008.05.001. View

13.

Vicente C, Cardoso da Silva T, Pereira L, Miranda A . Impact of concurrent epidemics of dengue, chikungunya, zika, and COVID-19. Rev Soc Bras Med Trop. 2021; 54:e08372020. PMC: 8008862. DOI: 10.1590/0037-8682-0837-2020. View

14.

Botta L, Rivara M, Zuliani V, Radi M . Drug repurposing approaches to fight Dengue virus infection and related diseases. Front Biosci (Landmark Ed). 2017; 23(6):997-1019. DOI: 10.2741/4630. View

15.

Castiglione V, Chiriaco M, Emdin M, Taddei S, Vergaro G . Statin therapy in COVID-19 infection. Eur Heart J Cardiovasc Pharmacother. 2020; 6(4):258-259. PMC: 7197622. DOI: 10.1093/ehjcvp/pvaa042. View

16.

Carette J, Raaben M, Wong A, Herbert A, Obernosterer G, Mulherkar N . Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature. 2011; 477(7364):340-3. PMC: 3175325. DOI: 10.1038/nature10348. View

17.

Bley H, Schobel A, Herker E . Whole Lotta Lipids-from HCV RNA Replication to the Mature Viral Particle. Int J Mol Sci. 2020; 21(8). PMC: 7215355. DOI: 10.3390/ijms21082888. View

18.

Rothwell C, Lebreton A, Ng C, Lim J, Liu W, Vasudevan S . Cholesterol biosynthesis modulation regulates dengue viral replication. Virology. 2009; 389(1-2):8-19. DOI: 10.1016/j.virol.2009.03.025. View

19.

San-Juan-Vergara H, Sampayo-Escobar V, Reyes N, Cha B, Pacheco-Lugo L, Wong T . Cholesterol-rich microdomains as docking platforms for respiratory syncytial virus in normal human bronchial epithelial cells. J Virol. 2011; 86(3):1832-43. PMC: 3264380. DOI: 10.1128/JVI.06274-11. View

20.

Soto-Acosta R, Bautista-Carbajal P, Cervantes-Salazar M, Angel-Ambrocio A, Del Angel R . DENV up-regulates the HMG-CoA reductase activity through the impairment of AMPK phosphorylation: A potential antiviral target. PLoS Pathog. 2017; 13(4):e1006257. PMC: 5383345. DOI: 10.1371/journal.ppat.1006257. View