Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production

Fintelman-Rodrigues, Natália; Sacramento, Carolina Q.; Lima, Carlyle Ribeiro; Souza-Silva, Franklin; Ferreira, André C.; Mattos, Mayara; Freitas, Caroline de; Soares, Vinícius Cardoso; Dias, Suelen da Silva Gomes; Temerozo, Jairo R.; Miranda, Mauro Sayão de; Matos, Aline da Rocha; Bozza, Fernando A.; Carels, Nicolas; Alves, Carlos Roberto; Siqueira, Marilda M.; Bozza, Patrı́cia T.; Souza, Thiago Moreno L.

doi:10.1101/2020.04.04.020925

Cited by 61 publications

(69 citation statements)

References 49 publications

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“…We identified 14 key studies that detailed the antiviral activity of 71 compounds. [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] The majority of the in vitro SARS-CoV-2 infection experiments were performed in Vero E6 cells (ATCC 1586) maintained in either Dulbecco's Modified Eagle's Medium or Minimum Essential Medium. Other studies utilized Vero-hSLAM cells, Vero E6 cells expressing TMPRSS2, and the CACO-2 cell line to cultivate the virus.…”

Section: Identified Papers and Methodsmentioning

confidence: 99%

Prioritization of Anti‐SARS‐Cov‐2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics

Arshad

Pertinez

Box

et al. 2020

Clin Pharma and Therapeutics

137

148

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There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans. Accordingly, concentration 90% (EC90) values recalculated from in vitro anti‐SARS‐CoV‐2 activity data was expressed as a ratio to the achievable maximum plasma concentration (Cmax) at an approved dose in humans (Cmax/EC90 ratio). Only 14 of the 56 analyzed drugs achieved a Cmax/EC90 ratio above 1. A more in‐depth assessment demonstrated that only nitazoxanide, nelfinavir, tipranavir (ritonavir‐boosted), and sulfadoxine achieved plasma concentrations above their reported anti‐SARS‐CoV‐2 activity across their entire approved dosing interval. An unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated to derive a lung Cmax/half‐maximal effective concentration (EC50) as a better indicator of potential human efficacy. Hydroxychloroquine, chloroquine, mefloquine, atazanavir (ritonavir‐boosted), tipranavir (ritonavir‐boosted), ivermectin, azithromycin, and lopinavir (ritonavir‐boosted) were all predicted to achieve lung concentrations over 10‐fold higher than their reported EC50. Nitazoxanide and sulfadoxine also exceeded their reported EC50 by 7.8‐fold and 1.5‐fold in lung, respectively. This analysis may be used to select potential candidates for further clinical testing, while deprioritizing compounds unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments, such as the lungs, in order to maximize the potential for success of proposed human clinical trials.

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Section: Identified Papers and Methodsmentioning

confidence: 99%

Prioritization of Anti‐SARS‐Cov‐2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics

Arshad

Pertinez

Box

et al. 2020

Clin Pharma and Therapeutics

137

148

View full text Add to dashboard Cite

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“…Dysregulated immune response with key involvement of monocytes, with increased pro-inflammatory cytokine/chemokine production is also observed during severe COVID-19 and is associated with the outcome of the disease (Coperchini et al, 2020;Zhou et al, 2020a). SARS-CoV-2 infection of human monocytes in vitro recapitulate most of the pattern of inflammatory mediator production associated with COVID-19 severity, including the enhancement of the IL-6 and TNFα levels, and the consistent cell death, measured by LDH release (Fintelman-Rodrigues et al, 2020;Temerozo et al, 2020;Zhou et al, 2020a). We showed the SARS-CoV-2 infection was able to generate a large amount of inflammatory lipid mediators, and cytokine synthesis by monocytes.…”

Section: Discussionmentioning

confidence: 95%

“…It has already been demonstrated the capacity of the SARS-CoV-2 infection to induce cell death in monocytes, measured by the release of LDH in the supernatant (Fintelman-Rodrigues et al, 2020). Cell death after infection can occur due to cellular dysfunctions that lead to changes in cellular homeostasis caused by the virus replication and/or by the heightened inflammatory response.…”

Section: Sars-cov-2 Infected Monocytesmentioning

confidence: 99%

Lipid droplets fuel SARS-CoV-2 replication and production of inflammatory mediators

Dias

Soares

Ferreira

et al. 2020

Preprint

Self Cite

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Viruses are obligate intracellular parasites that make use of the host metabolic machineries to meet their biosynthetic needs, identifying the host pathways essential for the virus replication may lead to potential targets for therapeutic intervention. The mechanisms and pathways explored by SARS-CoV-2 to support its replication within host cells are not fully known. Lipid droplets (LD) are organelles with major functions in lipid metabolism and energy homeostasis, and have multiple roles in infections and inflammation. Here we demonstrate that monocytes from COVID-19 patients have an increased LD accumulation compared to SARS-CoV-2 negative donors. In vitro, SARS-CoV-2 infection modulates pathways of lipid synthesis and uptake, as CD36, SREBP-1, PPARγ and DGAT-1 in human monocytes and triggered LD formation in different human cells. LDs were found in close apposition with SARS-CoV-2 proteins and double-stranded (ds)-RNA. The pharmacological modulation of LD formation by inhibition of DGAT-1 with A922500 significantly inhibited SARS-CoV-2 replication as well as reduced production of pro-inflammatory mediators. Taken together, we demonstrate the essential role of lipid metabolic reprograming and LD formation in SARS-CoV-2 replication and pathogenesis, opening new opportunities for therapeutic strategies to COVID-19.

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“…We identified 14 key studies that detailed the antiviral activity of 72 compounds [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] Table 1.…”

Section: Identified Papers and Methodsmentioning

confidence: 99%

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

Arshad

Pertinez

Box

et al. 2020

Preprint

View full text Add to dashboard Cite

There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, this has not been accompanied by a comprehensive evaluation of the ability of these drugs to achieve target plasma and lung concentrations following approved dosing in humans. Moreover, most publications have focussed on 50% maximum effective concentrations (EC50), which may be an insufficiently robust indicator of antiviral activity because of marked differences in the slope of the concentration-response curve between drugs. Accordingly, in vitro anti-SARS-CoV-2 activity data was digitised from all available publications up to 13 th April 2020 and used to recalculate an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90 ratio). Only 14 of the 56 analysed drugs achieved a Cmax/EC90 ratio above 1 meaning that plasma Cmax concentrations exceeded those necessary to inhibit 90% of SARS-CoV-2 replication. A more in-depth assessment of the putative agents tested demonstrated that only nitazoxanide, nelfinavir, tipranavir (boosted with ritonavir) and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval at their approved human dose. For all drugs reported, the unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated and used along with reported Cmax and fraction unbound in plasma to derive a lung Cmax/EC50 as a better indicator of potential human efficacy (lung Cmax/EC90 ratio was also calculable for a limited number of drugs). Using this parameter hydroxychloroquine, chloroquine, mefloquine, atazanavir (boosted with ritonavir), tipranavir (boosted with ritonavir), ivermectin, azithromycin and lopinavir (boosted with ritonavir) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50. This analysis was not possible for nelfinavir because insufficient data were available to calculate KpUlung but nitozoxanide and sulfadoxine were also predicted to exceed their reported EC50 by 3.1-and 1.5-fold in lung, respectively. The antiviral activity data reported to date have been acquired under different laboratory conditions across multiple groups, applying variable levels of stringency. However, this analysis may be used to select potential candidates for further clinical testing, while deprioritising compounds which are unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments such as the lung, in order to maximise the potential for success of proposed human clinical trials.

show abstract

Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production

Cited by 61 publications

References 49 publications

Prioritization of Anti‐SARS‐Cov‐2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics

Prioritization of Anti‐SARS‐Cov‐2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics

Lipid droplets fuel SARS-CoV-2 replication and production of inflammatory mediators

Prioritisation of potential anti-SARS-CoV-2 drug repurposing opportunities based on ability to achieve adequate plasma and target site concentrations derived from their established human pharmacokinetics

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