Abstract
Huperzine A is a bioactive compound derived from traditional Chinese medicine plant Qian Ceng Ta (Huperzia serrata), and was found to have multiple neuroprotective effects. In addition to being a potent acetylcholinesterase inhibitor, it was thought to act through other mechanisms such as antioxidation, antiapoptosis, etc. However, the molecular targets involved with these mechanisms were not identified. In this study, we attempted to exam the interactome of Huperzine A using a cDNA phage display library and also mammalian brain tissue extracts. The drugs were chemically linked on the surface of magnetic particles and the interactive phages or proteins were collected and analyzed. Among the various cDNA expressing phages selected, one was identified to encode the mitochondria NADH dehydrogenase subunit 1. Specific bindings between the drug and the target phages and target proteins were confirmed. Another enriched phage clone was identified as mitochondria ATP synthase, which was also panned out from the proteome of mouse brain tissue lysate. These data indicated the possible involvement of mitochondrial respiratory chain matrix enzymes in Huperzine A's pharmacological effects. Such involvement had been suggested by previous studies based on enzyme activity changes. Our data supported the new mechanism. Overall we demonstrated the feasibility of using magnetic biopanning as a simple and viable method for investigating the complex molecular mechanisms of bioactive molecules.
Highlights
Huperzine A (Hup A) is a compound found in the traditional Chinese medicine plant Qian Ceng Ta (Huperzia serrata) and has been shown to have neuroprotective effects [1,2] in Alzheimer disease (AD) patients
Drugs were conjugated to the magnetic particles (MPs) via the free carboxyl groups on polymers associated with MPs
Bioactive molecules identified from natural products have been an important source for drug discovery [20]
Summary
Huperzine A (Hup A) is a compound found in the traditional Chinese medicine plant Qian Ceng Ta (Huperzia serrata) and has been shown to have neuroprotective effects [1,2] in Alzheimer disease (AD) patients. It is a potent inhibitor of acetylcholinesterase(AChE) [3]. In order to identify the potential target molecules involved in these effects, Lun Yang and his coworkers published an interesting study of virtual chemicalprotein interactome (CPI) analysis, in which they evaluated the possible interactions between Hup A and 401 human protein pockets using the DOCK program [11]. Besides the only validated target AChE, several other putative targets were indicated to suggest some ‘‘behind-the-scenes’’ therapeutic mechanisms of Hup A
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