Predictive Systems Biology Approach to Broad-Spectrum, Host-Directed Drug Target Discovery in Infectious Diseases

Abstract

Knowledge of immune system and host-pathogen pathways can inform development of targeted therapies and molecular diagnostics based on a mechanistic understanding of disease pathogenesis and the host response. We investigated the feasibility of rapid target discovery for novel broad-spectrum molecular therapeutics through comprehensive systems biology modeling and analysis of pathogen and host-response pathways and mechanisms. We developed a system to identify and prioritize candidate host targets based on strength of mechanistic evidence characterizing the role of the target in pathogenesis and tractability desiderata that include optimal delivery of new indications through potential repurposing of existing compounds or therapeutics. Empirical validation of predicted targets in cellular and mouse model systems documented an effective target prediction rate of 34%, suggesting that such computational discovery approaches should be part of target discovery efforts in operational clinical or biodefense research initiatives. We describe our target discovery methodology, technical implementation, and experimental results. Our work demonstrates the potential for in silico pathway models to enable rapid, systematic identification and prioritization of novel targets against existing or emerging biological threats, thus accelerating drug discovery and medical countermeasures research. BackgroundNew and reemerging infectious diseases pose a growing global health risk across public health concerns and potential bioterrorism threats. Pandemic viruses, resistant bacteria, and technology improvements in bioengineering point to a need for accelerated drug discovery 1 . One approach to this challenge is to use computational techniques to efficiently identify drug targets that may effectively mount a defense against one or more biothreats 2 . Biologically diverse pathogens share common or similar mechanism of infection and pathogenesis, and the host has similarly conserved immune response biology [3][4][5] .We have previously demonstrated the broad applicability of systems biology analyses to drug discovery and development focused on mammalian disease biology [8][9][10] . We hypothesize that similar computational characterization of pathogen biology, pathogenesis and hostresponse genomic pathways across multiple infectious agents can enable systematic identification of targets of intervention that will impact multiple pathogens in a similar manner, and thus serve as broad-spectrum drug targets that can be modulated by novel or

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