Screening and Validation of Odorants against Influenza A Virus Using Interpretable Regression Models

Influenza is a respiratory infection caused by the influenza virus that is prevalent worldwide. One of the most contagious variants of influenza is influenza A virus (IAV), which usually spreads in closed spaces through aerosols. Preventive measures such as novel compounds are needed that can act on viral membranes and provide a safe environment against IAV infection. In this study, we screened compounds with common fragrances that are generally used to mask unpleasant odors but can also exhibit antiviral activity against a strain of IAV. Initially, a set of 188 structurally diverse odorants were collected, and their antiviral activity was measured in vapor phase against the IAV solution. Regression models were built for the prediction of antiviral activity using this set of odorants by taking into account their structural features along with vapor pressure and partition coefficient (n-octanol/water). The models were interpreted using a feature weighting approach and Shapley Additive exPlanations to rationalize the predictions as an additional validation for virtual screening. This model was used to screen odorants from an in-house odorant data set consisting of 2020 odorants, which were later evaluated using in vitro experiments. Out of 11 odorants proposed using the final model, 8 odorants were found to exhibit antiviral activity. The feature interpretation of screened odorants suggested that they contained hydrophilic substructures, such as hydroxyl group, which might contribute to denaturation of proteins on the surface of the virus. These odorants should be explored as a preventive measure in closed spaces to decrease the risk of infections of IAV

Multivariate analysis (Cox regression) for clinical and molecular variables of DFS and OS in CN-AML patients.

<p>CN-AML, cytogenetically normal acute myeloid leukemia; DFS, disease-free survival; OS, overall survival; CI, confidence interval; WT1^op, WT1 overexpression.</p>#<p>age ≤60 years vs. >60 years.</p><p>*P values <.05.</p

Determination of the diease-free survival (DFS) and overall survival (OS) in the CN-AML patients based on the <i>WT1</i> expression status and other molecular abnormalities.

<p>(<b>A–B</b>) Comparison of the DFS (<b>A</b>) and OS (<b>B</b>) between the CN-AML patients with normal (<i>WT1</i>^ctr) or high (<i>WT1</i>^op) <i>WT1</i> gene expression. The mean DFS and OS of patients with <i>WT1</i>^op (n = 29) or <i>WT1</i>^ctr (n = 74) were 18.9±2.1 <i>vs</i>. 27.8±1.4 mo (<i>p = .016</i>); and 23.6±2.3 <i>vs</i>. 32.5±1.3 mo (<i>p = .003</i>), respectively. (<b>C–D</b>) Comparison of the DFS (<b>C</b>) and OS (<b>D</b>) among three different risk subgroups that were stratified based on molecular abnormalities, <i>i.e</i>., the favorable risk group included CN-AML patients that are carrying the <i>NPM1</i>^mt/no <i>FLT3</i>^ITD genotypes; the unfavorable risk group with the <i>FLT3</i>^ITD genotypes; and the intermediate group are those patients other than the two other groups, <i>i.e</i>., lack of the <i>NPM1</i>^mt/no <i>FLT3</i>^ITD and <i>FLT3</i>^ITD genotypes <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092470#pone.0092470-Barragn1" target="_blank">[⁸]</a>. The average DFS of the patients with favorable (n = 23), intermediate (n = 62) or unfavorable genotype (n = 18) were 30.0±1.0, 26.6±1.6 and 13.9±3.0 mo, respectively. The average OS of the patients with favorable (n = 23), intermediate (n = 62) or unfavorable genotype (n = 18) were 34.2±0.85, 31.4±1.5 and 19.0±2.5 mo, respectively. (<b>E–J</b>) Possible role of <i>WT1</i> overexpression in determining the DFS (<b>E, G and I</b>) and OS (<b>F, H, and J</b>) among the favorable (<b>E–F</b>; <i>NPM1</i>^mt/no <i>FLT3</i>^ITD), the intermediate (<b>G–H</b>) and the unfavorable (<b>I–J</b>; <i>FLT3</i>^ITD) molecular and risk subgroups. Note that patients with <i>WT1</i>^op in the favorable (n = 4) or unfavorable (n = 8) had inferior DFS and OS than their control <i>WT1</i>^ctr groups (favorable, n = 19; unfavorable, n = 10). No significant differences of DFS and OS were observed between normal and high <i>WT1</i> gene expression in the intermediate group. Abbreviations: <i>WT1</i>^ctr, normal <i>WT1</i> expression; <i>WT1</i>^op, <i>WT1</i> overexpression.</p

Correlation of WT1 overexpression with clinical data, FAB subtypes, and molecular abnormalities in CN-AML patients.

<p>WT1^op, WT1 overexpression; FAB, French-American-British; CN-AML, cytogenetically normal acute myeloid leukemia; WBC, white blood cell.</p><p>*stratification based on molecular abnormalities <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0092470#pone.0092470-Lyu1" target="_blank">[2]</a>.</p