Endogenous-network-inspired Anti-psoriasis Drug Discovery

Psoriasis is a common chronic obstinate skin disease.The pathogenesis of psoriasis involves a serious of environmental factors,genes,regulation pathways and the interactions among them.However,there is still no model covered all these aspects.Endogenous network theory,which is a systems biological method,may be able to solve this problem.This theory states that functions of complex biological processes can be understood via an analysis of the network dynamic through a core regulatory network which can be reduced to a set of interactions between key regulators.The different kinetic steady states of a well-constructed network for certain disease could reflect the corresponding symptoms.In this work,based on the endogenous network for psoriasis,we tried to explore pathogenesis of the psoriasis,and found a new potential anti-psoriasis drug,astemizole.The anti-psoriasis activity of astemizole is confimed by an animal model,which lays the foundation for a new treatment for psoriasis.First,an endogenous network was constructed based on the symptom and key factors of psoriasis.The network consisted of three function modules: immune regulation,cell cycle control,and reactive oxygen species(ROS)balance.The dynamics simulation results were consistent with the features of psoriasis.This result indicated that the network could reveal the pathogenesis of psoriasis to a certain extent.The subsequent investigation showed not only the further evidence of the accuracy of the network by revealing that most of the FDA approved anti-psoriasis drugs were related to the immune regulation and cell cycle control,but also suggested that regulating ROS level could be a potential treatment for psoriasis because some potential therapeutic targets for psoriasis were included in the ROS blance module.Second,based on the connecative-map-based(c Map)drug repositioning analysis,we found some candidate Nrf2 activators.In order to reduce the cost of drug development and the risk of side effects,22 non-electrophilic approved drugs were selected from the candidate compounds and 9 of them were chosen to examine the Nrf2 activation ability by quantitative real-time PCR(q RT-PCR).Most of the tested drugs could significantly upregulate the expressin level of Nrf2 target genes.Astemizole showed the ability to activate Nrf2 even stronger than D,L-sulforaphane,which severed as the positive control.Last,the anti-psoriasis activity of astemizole was tested in an imiquimod-induced psoriatic mouse model.Astemizole could inhibit the desquamation,induration and acanthosis induced by imiquimod.Besides,some combination of astemizole and approved anti-psoriasis drug methotrexate exhibites better effect than the single drugs.In this study,a model characterizing the pathogenesis of psoriasis is constructed with a systems biological method.This model impired us to find a new potential anti-psoriasis drug,astemizole.The anti-psoriasis activity of astemizole is confimed in an animal model,laiding the foundation for a new treatment of psoriasis.