LanDis: the disease landscape explorer.

From a network medicine perspective, a disease is the consequence of perturbations on the interactome. These perturbations tend to appear in a specific neighbourhood on the interactome, the disease module, and modules related to phenotypically similar diseases tend to be located in close-by regions. We present LanDis, a freely available web-based interactive tool ( https://paccanarolab.org/landis ) that allows domain experts, medical doctors and the larger scientific community to graphically navigate the interactome distances between the modules of over 44 million pairs of heritable diseases. The map-like interface provides detailed comparisons between pairs of diseases together with supporting evidence. Every disease in LanDis is linked to relevant entries in OMIM and UniProt, providing a starting point for in-depth analysis and an opportunity for novel insight into the aetiology of diseases as well as differential diagnosis.

Unlike Chloroquine, Mefloquine Inhibits SARS-CoV-2 Infection in Physiologically Relevant Cells.

Despite the development of specific therapies against severe acute respiratory coronavirus 2 (SARS-CoV-2), the continuous investigation of the mechanism of action of clinically approved drugs could provide new information on the druggable steps of virus-host interaction. For example, chloroquine (CQ)/hydroxychloroquine (HCQ) lacks in vitro activity against SARS-CoV-2 in TMPRSS2-expressing cells, such as human pneumocyte cell line Calu-3, and likewise, failed to show clinical benefit in the Solidarity and Recovery clinical trials. Another antimalarial drug, mefloquine, which is not a 4-aminoquinoline like CQ/HCQ, has emerged as a potential anti-SARS-CoV-2 antiviral in vitro and has also been previously repurposed for respiratory diseases. Here, we investigated the anti-SARS-CoV-2 mechanism of action of mefloquine in cells relevant for the physiopathology of COVID-19, such as Calu-3 cells (that recapitulate type II pneumocytes) and monocytes. Molecular pathways modulated by mefloquine were assessed by differential expression analysis, and confirmed by biological assays. A PBPK model was developed to assess mefloquine's optimal doses for achieving therapeutic concentrations. Mefloquine inhibited SARS-CoV-2 replication in Calu-3, with an EC50 of 1.2 µM and EC90 of 5.3 µM. It reduced SARS-CoV-2 RNA levels in monocytes and prevented virus-induced enhancement of IL-6 and TNF-α. Mefloquine reduced SARS-CoV-2 entry and synergized with Remdesivir. Mefloquine's pharmacological parameters are consistent with its plasma exposure in humans and its tissue-to-plasma predicted coefficient points suggesting that mefloquine may accumulate in the lungs. Altogether, our data indicate that mefloquine's chemical structure could represent an orally available host-acting agent to inhibit virus entry.

Machine learning prediction of side effects for drugs in clinical trials.

Early and accurate detection of side effects is critical for the clinical success of drugs under development. Here, we aim to predict unknown side effects for drugs with a small number of side effects identified in randomized controlled clinical trials. Our machine learning framework, the geometric self-expressive model (GSEM), learns globally optimal self-representations for drugs and side effects from pharmacological graph networks. We show the usefulness of the GSEM on 505 therapeutically diverse drugs and 904 side effects from multiple human physiological systems. Here, we also show a data integration strategy that could be adopted to improve the ability of side effect prediction models to identify unknown side effects that might only appear after the drug enters the market.

Machine learning and network medicine approaches for drug repositioning for COVID-19.

We present two machine learning approaches for drug repurposing. While we have developed them for COVID-19, they are disease-agnostic. The two methodologies are complementary, targeting SARS-CoV-2 and host factors, respectively. Our first approach consists of a matrix factorization algorithm to rank broad-spectrum antivirals. Our second approach, based on network medicine, uses graph kernels to rank drugs according to the perturbation they induce on a subnetwork of the human interactome that is crucial for SARS-CoV-2 infection/replication. Our experiments show that our top predicted broad-spectrum antivirals include drugs indicated for compassionate use in COVID-19 patients; and that the ranking obtained by our kernel-based approach aligns with experimental data. Finally, we present the COVID-19 repositioning explorer (CoREx), an interactive online tool to explore the interplay between drugs and SARS-CoV-2 host proteins in the context of biological networks, protein function, drug clinical use, and Connectivity Map. CoREx is freely available at: https://paccanarolab.org/corex/.