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Proposal to Consider Chemical/Physical Microenvironment as a New Therapeutic Off-Target Approach

The molecular revolution could lead drug discovery from chance observation to the rational design of new classes of drugs that could simultaneously be more effective and less toxic. Unfortunately, we are witnessing some failure in this sense, and the causes of the crisis involve a wide range of epis...

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Autores principales: Giuliani, Alessandro, Fais, Stefano
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9611316/
https://www.ncbi.nlm.nih.gov/pubmed/36297518
http://dx.doi.org/10.3390/pharmaceutics14102084
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author Giuliani, Alessandro
Fais, Stefano
author_facet Giuliani, Alessandro
Fais, Stefano
author_sort Giuliani, Alessandro
collection PubMed
description The molecular revolution could lead drug discovery from chance observation to the rational design of new classes of drugs that could simultaneously be more effective and less toxic. Unfortunately, we are witnessing some failure in this sense, and the causes of the crisis involve a wide range of epistemological and scientific aspects. In pharmacology, one key point is the crisis of the paradigm the “magic bullet”, which is to design therapies based on specific molecular targets. Drug repurposing is one of the proposed ways out of the crisis and is based on the off-target effects of known drugs. Here, we propose the microenvironment as the ideal place to direct the off-targeting of known drugs. While it has been extensively investigated in tumors, the generation of a harsh microenvironment is also a phenotype of the vast majority of chronic diseases. The hostile microenvironment, on the one hand, reduces the efficacy of both chemical and biological drugs; on the other hand, it dictates a sort of “Darwinian” selection of those cells armed to survive in such hostile conditions. This opens the way to the consideration of the microenvironment as a convenient target for pharmacological action, with a clear example in proton pump inhibitors.
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spelling pubmed-96113162022-10-28 Proposal to Consider Chemical/Physical Microenvironment as a New Therapeutic Off-Target Approach Giuliani, Alessandro Fais, Stefano Pharmaceutics Perspective The molecular revolution could lead drug discovery from chance observation to the rational design of new classes of drugs that could simultaneously be more effective and less toxic. Unfortunately, we are witnessing some failure in this sense, and the causes of the crisis involve a wide range of epistemological and scientific aspects. In pharmacology, one key point is the crisis of the paradigm the “magic bullet”, which is to design therapies based on specific molecular targets. Drug repurposing is one of the proposed ways out of the crisis and is based on the off-target effects of known drugs. Here, we propose the microenvironment as the ideal place to direct the off-targeting of known drugs. While it has been extensively investigated in tumors, the generation of a harsh microenvironment is also a phenotype of the vast majority of chronic diseases. The hostile microenvironment, on the one hand, reduces the efficacy of both chemical and biological drugs; on the other hand, it dictates a sort of “Darwinian” selection of those cells armed to survive in such hostile conditions. This opens the way to the consideration of the microenvironment as a convenient target for pharmacological action, with a clear example in proton pump inhibitors. MDPI 2022-09-29 /pmc/articles/PMC9611316/ /pubmed/36297518 http://dx.doi.org/10.3390/pharmaceutics14102084 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Perspective
Giuliani, Alessandro
Fais, Stefano
Proposal to Consider Chemical/Physical Microenvironment as a New Therapeutic Off-Target Approach
title Proposal to Consider Chemical/Physical Microenvironment as a New Therapeutic Off-Target Approach
title_full Proposal to Consider Chemical/Physical Microenvironment as a New Therapeutic Off-Target Approach
title_fullStr Proposal to Consider Chemical/Physical Microenvironment as a New Therapeutic Off-Target Approach
title_full_unstemmed Proposal to Consider Chemical/Physical Microenvironment as a New Therapeutic Off-Target Approach
title_short Proposal to Consider Chemical/Physical Microenvironment as a New Therapeutic Off-Target Approach
title_sort proposal to consider chemical/physical microenvironment as a new therapeutic off-target approach
topic Perspective
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9611316/
https://www.ncbi.nlm.nih.gov/pubmed/36297518
http://dx.doi.org/10.3390/pharmaceutics14102084
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