Network-Based Approaches Reveal Potential Therapeutic Targets for Host-Directed Antileishmanial Therapy Driving Drug Repurposing
| Autor: | Vinicius Maracaja-Coutinho, Frank Kramer, Alessandra Mara de Sousa, Rubens L. Monte-Neto, Alberto J. M. Martin, Zaynab Hammoud, J. Eduardo Martinez-Hernandez |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Microbiology (medical)
Drug multilayered network Physiology media_common.quotation_subject Gene regulatory network Antiprotozoal Agents Computational biology Biology Microbiology Genetics medicine Humans Leishmania major gene regulatory networks Leishmaniasis Repurposing media_common General Immunology and Microbiology Ecology drug repurposing Gene Expression Profiling Macrophages Drug Repositioning host-direct therapy Cell Biology biology.organism_classification Leishmania medicine.disease QR1-502 Drug repositioning Infectious Diseases ddc:004 Transcriptome Function (biology) Metabolic Networks and Pathways Research Article |
| Zdroj: | Microbiology Spectrum Microbiology Spectrum, Vol 9, Iss 2 (2021) |
| ISSN: | 2165-0497 |
| Popis: | Leishmania parasites are the causal agent of leishmaniasis, an endemic disease in more than 90 countries worldwide. Over the years, traditional approaches focused on the parasite when developing treatments against leishmaniasis. Despite numerous attempts, there is not yet a universal treatment, and those available have allowed for the appearance of resistance. Here, we propose and follow a host-directed approach that aims to overcome the current lack of treatment. Our approach identifies potential therapeutic targets in the host cell and proposes known drug interactions aiming to improve the immune response and to block the host machinery necessary for the survival of the parasite. We started analyzing transcription factor regulatory networks of macrophages infected with Leishmania major. Next, based on the regulatory dynamics of the infection and available gene expression profiles, we selected potential therapeutic target proteins. The function of these proteins was then analyzed following a multilayered network scheme in which we combined information on metabolic pathways with known drugs that have a direct connection with the activity carried out by these proteins. Using our approach, we were able to identify five host protein-coding gene products that are potential therapeutic targets for treating leishmaniasis. Moreover, from the 11 drugs known to interact with the function performed by these proteins, 3 have already been tested against this parasite, verifying in this way our novel methodology. More importantly, the remaining eight drugs previously employed to treat other diseases, remain as promising yet-untested antileishmanial therapies. IMPORTANCE This work opens a new path to fight parasites by targeting host molecular functions by repurposing available and approved drugs. We created a novel approach to identify key proteins involved in any biological process by combining gene regulatory networks and expression profiles. Once proteins have been selected, our approach employs a multilayered network methodology that relates proteins to functions to drugs that alter these functions. By applying our novel approach to macrophages during the Leishmania infection process, we both validated our work and found eight drugs already approved for use in humans that to the best of our knowledge were never employed to treat leishmaniasis, rendering our work as a new tool in the box available to the scientific community fighting parasites. |
| Databáze: | OpenAIRE |
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