RESUMO
Repurposing pharmaceuticals is a technique used to find new, alternate clinical applications for approved drug molecules. It may include altering the drug formulation, route of administration, dose or the dosage regimen. The process of repurposing medicines starts with screening libraries of previously approved drugs for the targeted disease condition. If after an the initial in silico, in vitro or in vivo experimentation, the molecule has been found to be active against a particular target, the molecule is considered as a good candidate for clinical trials. As the safety profile of such molecules is available from the previous data, significant time and resources are saved. These advantages of drug repurposing approach make it especially helpful for finding treatments for rapidly evolving conditions including bacterial infections. An ever-increasing incidence of antimicrobial resistance, owing to the mutations in bacterial genome, leads to therapeutic failure of many approved antibiotics. Repurposing the approved drug molecules for use as antibiotics can provide an effective means for the combating life-threatening bacterial diseases. A number of drugs have been considered for drug repurposing against bacterial infections. These include, but are not limited to, Auranofin, Closantel, and Toremifene that have been repurposed for various infections. In addition, the reallocation of route of administration, redefining dosage regimen and reformulation of dosage forms have also been carried out for repurposing purpose. The current chapter addresses the drug discovery and development process with relevance to repurposing against bacterial infections.
Assuntos
Infecções Bacterianas , Reposicionamento de Medicamentos , Humanos , Infecções Bacterianas/tratamento farmacológico , Animais , Antibacterianos/uso terapêutico , Antibacterianos/farmacologiaRESUMO
The drug discovery and development (DDD) process greatly relies on the data available in various forms to generate hypotheses for novel drug design. The complex and heterogeneous nature of biological data makes it difficult to utilize or gather meaningful information as such. Computational biology techniques have provided us with opportunities to better understand biological systems through refining and organizing large amounts of data into actionable and systematic purviews. The drug repurposing approach has been utilized to overcome the expansive time periods and costs associated with traditional drug development. It deals with discovering new uses of already approved drugs that have an established safety and efficacy profile, thereby, requiring them to go through fewer development phases. Thus, drug repurposing through computational biology provides a systematic approach to drug development and overcomes the constraints of traditional processes. The current chapter covers the basics, approaches and tools of computational biology that can be employed to effectively develop repurposing profile of already approved drug molecules.
Assuntos
Biologia Computacional , Reposicionamento de Medicamentos , Humanos , Biologia Computacional/métodos , Descoberta de Drogas/métodosRESUMO
In the present study, we explored the development of a novel noninvasive liposomal drug delivery material for use in intranasal drug delivery applications in human diseases. We used drug entrapment into liposomal nanoparticle assembly to efficiently deliver the drugs to the nasal mucosa to be delivered to the brain. The naturally occurring flavonoid 7,8-dihydroxyflavone (7,8-DHF) has previously been shown to have beneficial effects in ameliorating Parkinson's disease (PD). We used both naturally occurring 7,8-DHF and the chemically modified form of DHF, the DHF-ME, to be used as a drug candidate for the treatment of PD and l-DOPA induced dyskinesia (LID), which is the debilitating side effect of l-DOPA therapy in PD. The ligand-protein interaction behavior for 7,8-DHF and 6,7-DHF-ME was found to be more effective with molecular docking and molecular stimulation studies of flavonoid compounds with TrkB receptor. Our study showed that 7,8-DHF delivered via intranasal route using a liposomal formulation ameliorated LID in hemiparkinsonian mice model when these mice were chronically administered with l-DOPA, which is the only current medication for relieving the clinical symptoms of PD. The present study also demonstrated that apart from reducing the LID, 7,8-DHF delivery directly to the brain via the intranasal route also corrected some long-term signaling adaptations involving ΔFosB and α Synuclein in the brain of dopamine (DA) depleted animals.
Assuntos
Administração Intranasal , Flavonoides , Levodopa , Lipossomos , Animais , Lipossomos/química , Levodopa/administração & dosagem , Flavonoides/administração & dosagem , Flavonoides/farmacologia , Camundongos , Masculino , Doença de Parkinson/tratamento farmacológico , Camundongos Endogâmicos C57BL , Discinesia Induzida por Medicamentos/tratamento farmacológico , Simulação de Acoplamento Molecular , Receptor trkB/metabolismo , Sistemas de Liberação de Medicamentos , FlavonasRESUMO
Innate immunity, the first line of defense against pathogens, relies on efficient elimination of invading agents by phagocytes. In the co-evolution of host and pathogen, pathogens developed mechanisms to dampen and evade phagocytic clearance. Here, we report that bacterial pathogens can evade clearance by macrophages through mimicry at the mammalian anti-phagocytic "don't eat me" signaling axis between CD47 (ligand) and SIRPα (receptor). We identified a protein, P66, on the surface of Borrelia burgdorferi that, like CD47, is necessary and sufficient to bind the macrophage receptor SIRPα. Expression of the gene encoding the protein is required for bacteria to bind SIRPα or a high-affinity CD47 reagent. Genetic deletion of p66 increases phagocytosis by macrophages. Blockade of P66 during infection promotes clearance of the bacteria. This study demonstrates that mimicry of the mammalian anti-phagocytic protein CD47 by B. burgdorferi inhibits macrophage-mediated bacterial clearance. Such a mechanism has broad implications for understanding of host-pathogen interactions and expands the function of the established innate immune checkpoint receptor SIRPα. Moreover, this report reveals P66 as a novel therapeutic target in the treatment of Lyme Disease.