Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models

Oya, Nereida Jiménez de; Esler, William P.; Huard, Kim; El‐Kattan, Ayman; Karamanlidis, Georgios; Blázquez, Ana-Belén; Ramos‐Ibeas, Priscila; Escribano-Romero, Estela; Louloudes-Lázaro, Andrés; Casas, Josefina; Sánchez‐Madrid, Francisco; Hoehn, Kyle L.; James, David E.; Gutiérrez‐Adán, Alfonso; Sáiz, Juan‐Carlos; Martín-Acebes, Miguel A.

doi:10.1080/22221751.2019.1604084

Cited by 33 publications

(35 citation statements)

References 58 publications

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“…For instance, both extracellular and intracellular arthropod-borne pathogens must salvage lipids from their hosts for survival ( Table 2 ). To this end, drugs targeting lipid metabolism have been shown to inhibit arboviral and parasitic infections ( Tewary et al, 2006 ; Bobenchik et al, 2013 ; Merino-Ramos et al, 2016 ; Choi et al, 2016 ; Jiménez de Oya et al, 2019 ). Thus, their use in humans is a promising area of research.…”

Section: Conclusion and Perspectivementioning

confidence: 99%

Lipid hijacking: A unifying theme in vector-borne diseases

O’Neal

Butler

Rolandelli

et al. 2020

eLife

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Vector-borne illnesses comprise a significant portion of human maladies, representing 17% of global infections. Transmission of vector-borne pathogens to mammals primarily occurs by hematophagous arthropods. It is speculated that blood may provide a unique environment that aids in the replication and pathogenesis of these microbes. Lipids and their derivatives are one component enriched in blood and are essential for microbial survival. For instance, the malarial parasite Plasmodium falciparum and the Lyme disease spirochete Borrelia burgdorferi, among others, have been shown to scavenge and manipulate host lipids for structural support, metabolism, replication, immune evasion, and disease severity. In this Review, we will explore the importance of lipid hijacking for the growth and persistence of these microbes in both mammalian hosts and arthropod vectors.

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Section: Conclusion and Perspectivementioning

confidence: 99%

Lipid hijacking: A unifying theme in vector-borne diseases

O’Neal

Butler

Rolandelli

et al. 2020

eLife

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“…The activation of AMPK using these compounds also inhibits the infection of DENV and WNV [51,53], confirming the broad-spectrum antiviral potential of this kind of drugs. Results using a series of small-molecule inhibitors (PF-05175157, PF-05206574 and PF-06256254, Table 1) of acetyl-Coenzyme A carboxylase (ACC), the key enzyme of fatty acid metabolism, support the role of lipid metabolism and specifically fatty acid synthesis in ZIKV, DENV, and WNV infection [54]. One of these inhibitors, PF-05175157, which has undergone clinical trials in healthy volunteers (NCT01433380), and for the treatment of diabetes mellitus (NCT01792635), was tested against WNV in mouse models, showing a reduction of viremia and viral load in the kidney, suggesting the potential of these compounds for the treatment of flavivirus diseases.…”

Section: Lipids and Therapeutic Opportunities Against Zikv Infectionmentioning

confidence: 99%

Lipid Metabolism as a Source of Druggable Targets for Antiviral Discovery against Zika and Other Flaviviruses

2019

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The Zika virus (ZIKV) is a mosquito-borne flavivirus that can lead to birth defects (microcephaly), ocular lesions and neurological disorders (Guillain-Barré syndrome). There is no licensed vaccine or antiviral treatment against ZIKV infection. The effort to understand the complex interactions of ZIKV with cellular networks contributes to the identification of novel host-directed antiviral (HDA) candidates. Among the cellular pathways involved in infection, lipid metabolism gains attention. In ZIKV-infected cells lipid metabolism attributed to intracellular membrane remodeling, virion morphogenesis, autophagy modulation, innate immunity and inflammation. The key roles played by the cellular structures associated with lipid metabolism, such as peroxisomes and lipid droplets, are starting to be deciphered. Consequently, there is a wide variety of lipid-related antiviral strategies that are currently under consideration, which include an inhibition of sterol regulatory element-binding proteins (SREBP), the activation of adenosine-monophosphate activated kinase (AMPK), an inhibition of acetyl-Coenzyme A carboxylase (ACC), interference with sphingolipid metabolism, blockage of intracellular cholesterol trafficking, or a treatment with cholesterol derivatives. Remarkably, most of the HDAs identified in these studies are also effective against flaviviruses other than ZIKV (West Nile virus and dengue virus), supporting their broad-spectrum effect. Considering that lipid metabolism is one of the main cellular pathways suitable for pharmacological intervention, the idea of repositioning drugs targeting lipid metabolism as antiviral candidates is gaining force.

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“…Next, palmitate undergoes chain propagation to produce saturated FAs via FA elongase [43], as seen in Figure 7. It is common to suppress FA synthesis by inhibitors targeting related enzymes, which have been proven to decrease the replication of various viruses, including respiratory viruses [44] and flaviviruses [45]. Additionally, evidence has shown that drugs targeting ACC1 are effective for antiviral treatment [46][47][48].…”

Section: Discussionmentioning

confidence: 99%

Fatty Acids Regulate Porcine Reproductive and Respiratory Syndrome Virus Infection via the AMPK-ACC1 Signaling Pathway

Long

Zhou

Bai

et al. 2019

Viruses

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Lipids play a crucial role in the replication of porcine reproductive and respiratory syndrome virus (PRRSV), a porcine virus that is endemic throughout the world. However, little is known about the effect of fatty acids (FAs), a type of vital lipid, on PRRSV infection. In this study, we found that treatment with a FA biosynthetic inhibitor significantly inhibited PRRSV propagation, indicating the necessity of FAs for optimal replication of PRRSV. Further study revealed that 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK), a key kinase antagonizing FA biosynthesis, was strongly activated by PRRSV and the pharmacological activator of AMPK exhibited anti-PRRSV activity. Additionally, we found that acetyl-CoA carboxylase 1 (ACC1), the first rate-limiting enzyme in the FA biosynthesis pathway, was phosphorylated (inactive form) by PRRSV-activated AMPK, and active ACC1 was required for PRRSV proliferation, suggesting that the PRRSV infection induced the activation of the AMPK–ACC1 pathway, which was not conducive to PRRSV replication. This work provides new evidence about the mechanisms involved in host lipid metabolism during PRRSV infection and identifies novel potential antiviral targets for PRRSV.

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Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models

Cited by 33 publications

References 58 publications

Lipid hijacking: A unifying theme in vector-borne diseases

Lipid hijacking: A unifying theme in vector-borne diseases

Lipid Metabolism as a Source of Druggable Targets for Antiviral Discovery against Zika and Other Flaviviruses

Fatty Acids Regulate Porcine Reproductive and Respiratory Syndrome Virus Infection via the AMPK-ACC1 Signaling Pathway

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