Abstract
Drug discovery is a complex process, and the use of a comprehensive approach is deemed necessary to discover new chemical entities with novel mechanisms of action. This research was carried out to determine whether Drosophila melanogaster can serve as an appropriate model organism in the initial screening of drug candidates with immunomodulatory activities. To test this, we performed phenotypic assay and molecular analysis to investigate the immunomodulatory activities of aspirin, dexamethasone, curcumin, and epigallocatechin gallate (EGCG), that have been reported to yield such effects in the mammalian model system. In vivo survival analysis demonstrated that all drugs/compounds were relatively safe at the tested concentrations. In the infection assay, curcumin and EGCG showed a protective signature to bacterial infection in flies lacking Toll-mediated immune responses. Furthermore, dexamethasone and aspirin, drugs with immunosuppressive activity, could improve the survival of PGRP-LBΔ mutant flies with hyperactivated immune system. These phenotypes were supported by RT-qPCR-based molecular analysis, revealing that drugs/compounds used in this study could modulate the expression level of genes related to the immune system. In conclusion, while curcumin and EGCG could promote the improvement of fly survival against infection, aspirin and dexamethasone were able to suppress overactivation of immune responses in D. melanogaster. These results are in line with the ones observed in the mammalian model system, further emphasizing the notion that flies would serve as a prospective model organism in the initial screening of drug candidates for their immunomodulatory activities prior to further checking in the mammalian animal models. In the end, this will reduce the use of mammalian animal models for preliminary experiments in an effort to discover/repurpose drugs with immunomodulatory activity.
Highlights
Drug discovery is a complex process, and the use of a comprehensive approach is deemed necessary to discover new chemical entities with novel mechanisms of action from nature [1]
InIn this study, we demonstrated that melanogaster is is a prospective model toto screen this study, we demonstrated that melanogaster a prospective model screen immunomodulatory drug candidates and the same time demonstrate whether such immunomodulatory drug candidates and atat the same time demonstrate whether such candidatesalso exert exert antibacterial observed thatthat curcumin and epigallocatechin gallate (EGCG)
We examined the immunomodulatory activities of two synthetic drugs and two natural products, which have been previously reported to exert such effect in the mammalian animal models [37,39,40,41]
Summary
Drug discovery is a complex process, and the use of a comprehensive approach is deemed necessary to discover new chemical entities with novel mechanisms of action from nature [1]. The current approach used in the discovery of new immunomodulators is a combination of in silico, in vitro, and in vivo pre-clinical experiments in appropriate animal models prior to clinical testing in humans [2,3]. Stimulation of host immune responses to certain antigens/pathogenic cues through vaccination is the most effective method of protecting a host from infection [4]. Activation of host innate cellular and humoral immunity by agonists with immunomodulatory activities has been a pertinent approach to developing a rapid and broad protective effector against pathogenic microbes [3]
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