Drug combination sensitivity scoring facilitates the discovery of synergistic and efficacious drug combinations in cancer

Malyutina, Alina; Majumder, Muntasir Mamun; Wang, Wenyu; Pessia, Alberto; Heckman, Caroline A.; Tang, Jing

doi:10.1101/512244

Cited by 15 publications

(4 citation statements)

References 36 publications

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“…Synergy scores were estimated using four different methods (ZIP, Loewe, HSA, and Bliss) and both the cobicistat/nirmatrelvir and the ritonavir/nirmatrelvir combinations displayed similar, pan-variant, synergism (Figure 6, Figure S4) which was more evident in the highest range of the tested concentrations (5-20µM) of cobicistat and ritonavir (Figure S4). The potency of each drug combination was then analyzed by calculating combination sensitivity scores (CSS), as previously described (Malyutina et al, 2019). Of note, cobicistat/nirmatrelvir showed a significantly higher combination sensitivity score than ritonavir/nirmatrelvir (Figure 6), suggesting enhanced suppression of SARS-CoV-2 replication across the range of concentrations tested, and in line with the increased potency of single treatment with cobicistat (i.e.…”

Section: Higher Sars-cov-2 Inhibition Through Nirmatrelvir/cobicistat...mentioning

confidence: 74%

“…Drug interaction scores were evaluated using the web tool SynergyFinder plus (Zheng et al, 2022). Parameters analyzed included synergy (ZIP, Loewe, HSA, and Bliss models) and combination sensitivity (Malyutina et al, 2019). The relationship between maximal inhibition values and baseline infection was assessed by Spearman correlation, while pairwise comparisons were analyzed by paired t-test.…”

Section: Discussionmentioning

confidence: 99%

“…While synergy provides an estimate of drug interactions, it does not necessarily capture therapeutic efficacy, which is arguably a more important parameter for real-world applications of drug combinations (Malyutina et al, 2019). Towards this purpose, we employed the previously described CSS parameter (Malyutina et al, 2019) and found that the cobicistat/nirmatrelvir combination induces a significantly more potent suppression of SARS-CoV-2 replication. On the other hand, CSS values for both combinations were similar when considering HCoV-229E and MERS-CoV.…”

Section: Discussionmentioning

confidence: 99%

“…The data shown in Figures 4 and 5 were used to calculate the relative inhibition of viral replication induced by each drug or drug combination, as compared to vehicle (DMSO) controls. Inhibition levels were used to compute synergy (ZIP, Loewe, HSA, and Bliss models), relative inhibition (RI) by single treatment with cobicistat or ritonavir and combination sensitivity scores (CSS)(Malyutina et al, 2019) using the SynergyFinder plus software(Zheng et al, 2022). The scores obtained with cobicistat (with nirmatrelvir) or ritonavir (with nirmatrelvir) were then compared by paired t-test.…”

mentioning

confidence: 99%

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Broad-spectrum antiviral activity of clinically approved CYP3A inhibitors against pathogenic human coronaviruses in vitro

Gallucci,

Bazire,

Davidson

et al. 2023

Preprint

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Coronaviruses pose a permanent risk of outbreaks, with three highly pathogenic species and strains (SARS-CoV, MERS-CoV, SARS-CoV-2) having emerged in the last twenty years. Limited antiviral therapies are currently available and their efficacy in randomized clinical trials enrolling SARS-CoV-2 patients has not been consistent, highlighting the need for more potent treatments. We previously showed that cobicistat, a clinically approved inhibitor of Cytochrome P450-3A (CYP3A), has direct antiviral activity against early circulating SARS-CoV-2 strains in vitro and in Syrian hamsters. Cobicistat is a derivative of ritonavir, which is co-administered as pharmacoenhancer with the SARS-CoV-2 protease inhibitor nirmatrelvir, to inhibit its metabolization by CPY3A and preserve its antiviral efficacy. Here, we used automated imaging and analysis for a screening and parallel comparison of the anti-coronavirus effects of cobicistat and ritonavir. Our data show that both drugs display antiviral activity at low micromolar concentrations against multiple SARS-CoV-2 variants in vitro, including epidemiologically relevant Omicron subvariants. Despite their close structural similarity, we found that cobicistat is more potent than ritonavir, as shown by significantly lower EC50 values in monotherapy and higher levels of viral suppression when used in combination with nirmatrelvir. Finally, we show that the antiviral activity of both cobicistat and ritonavir is maintained against other human coronaviruses, including HCoV-229E and the highly pathogenic MERS-CoV. Overall, our results demonstrate that cobicistat has more potent anti-coronavirus activity than ritonavir and suggest that dose adjustments could pave the way to the use of both drugs as broad-spectrum antivirals against highly pathogenic human coronaviruses.

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Section: Higher Sars-cov-2 Inhibition Through Nirmatrelvir/cobicistat...mentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Broad-spectrum antiviral activity of clinically approved CYP3A inhibitors against pathogenic human coronaviruses in vitro

Gallucci,

Bazire,

Davidson

et al. 2023

Preprint

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Drug synergy of combinatory treatment with remdesivir and the repurposed drugs fluoxetine and itraconazole effectively impairs SARS-CoV-2 infection in vitro

Schloer¹,

Brunotte²,

Mecate-Zambrano³

et al. 2020

Preprint

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The SARS-COV-2 pandemic and the global spread of coronavirus disease 2019 (COVID-19) urgently calls for efficient and safe antiviral treatment strategies. A straightforward approach to speed up drug development at lower costs is drug repurposing. Here we investigated the therapeutic potential of targeting the host- SARS-CoV-2 interface via repurposing of clinically licensed drugs and evaluated their use in combinatory treatments with virus- and host-directed drugs. We tested the antiviral potential of repurposing the antifungal itraconazole and the antidepressant fluoxetine on the production of infectious SARS-CoV-2 particles in the polarized Calu-3 cell culture model and evaluated the added benefit of a combinatory use of these host-directed drugs with remdesivir, an inhibitor of viral RNA polymerase. Drug treatments were well-tolerated and potent impaired viral replication was observed with all drug treatments. Importantly, both itraconazole-remdesivir and fluoxetine-remdesivir combinations inhibited the production of infectious SARS-CoV-2 particles > 90% and displayed synergistic effects in commonly used reference models for drug interaction. Itraconazole-Remdesivir and Fluoxetine-Remdesivir combinations are promising therapeutic options to control SARS-CoV-2 infection and severe progression of COVID-19.

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Nonmetric ANOVA: a generic framework for analysis of variance on dissimilarity measures

Malyutina

Tang

Amiryousefi

2021

Preprint

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Classic Analysis of Variance (ANOVA; cA) tests the explanatory power of a partitioning on a set of objects. Nonparametric ANOVA (npA) extends to a case where instead of the object values themselves, their mutual distances are available. While considerably widening the applicability of the cA, the npA does not provide a statistical framework for the cases where the mutual dissimilarity measurements between objects are nonmetric. Based on the central limit theorem (CLT), we introduce nonmetric ANOVA (nmA) as an extension of the cA and npA models where metric properties (identity, symmetry, and subadditivity) are relaxed. Our model allows any dissimilarity measures to be defined between objects where a distinctiveness of a specific partitioning imposed on those are of interest. This derivation accommodates an ANOVA-like framework of judgment, indicative of significant dispersion of the partitioned outputs in nonmetric space. We present a statistic which under the null hypothesis of no differences between the mean of the imposed partitioning, follows an exact F-distribution allowing to obtain the consequential p-value. Three biological examples are provided and the performance of our method in relation to the cA and npA is discussed.Significance StatementThe Nonmetric Analysis of Variance (nmANOVA) conveys a framework that allows a compatible type of ANOVA for the cases where the proper metric measurements between objects are either lost, unknown or however inaccessible. While classic ANOVA is based on the measurements of the data from a base datum, the nmANOVA is formulated on the dissimilarity outputs (not necessarily metric) defined between all objects. As the main goal of ANOVA in providing a statistical test for assessing the significance of a considered partitioning on the data, the nmANOVA is yielding a paralleled scheme of inference with 1) accommodating the outcomes dissimilarities into within and between groups statistics, 2) assessing their respective divergence with a parametric distribution, and 3) providing a resultant p-value indicative of evidences fore rejecting the null hypothesis.

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Drug combination sensitivity scoring facilitates the discovery of synergistic and efficacious drug combinations in cancer

Cited by 15 publications

References 36 publications

Broad-spectrum antiviral activity of clinically approved CYP3A inhibitors against pathogenic human coronaviruses in vitro

Broad-spectrum antiviral activity of clinically approved CYP3A inhibitors against pathogenic human coronaviruses in vitro

Drug synergy of combinatory treatment with remdesivir and the repurposed drugs fluoxetine and itraconazole effectively impairs SARS-CoV-2 infection in vitro

Nonmetric ANOVA: a generic framework for analysis of variance on dissimilarity measures

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