title: A novel assay for screening inhibitors targeting HIV-1 integrase dimerization based on Ni-NTA magnetic agarose beads.
abstract: Human immunodeficiency virus (HIV)-1 integrase (IN), which mediates integration of viral cDNA into the cellular chromosome, is a validated antiviral drug target. Three IN inhibitors, raltegravir, elvitegravir and dolutegravir, have been clinically approved since 2008. However, drug resistance have emerged in infected patients receiving treatment using these drugs which share the same mechanism of action and have a low genetic barrier for resistance. Therefore, there is an urgent need to develop drugs with novel mechanism. IN requires a precise and dynamic equilibrium between several oligomeric species for its activities. The modulation of the process which is termed as IN oligomerization, presents an interesting allosteric target for drug development. In this research, we developed a magnetic beads based approach to assay the IN dimerization. Then, using the assay we screened a library of 1000 Food and Drug Administration (FDA)-approved drugs for IN dimerization inhibitors and identified dexlansoprazole as a potential IN dimerization inhibitor. In conclusion, the assay presented here has been proven to be sensitive and specific for the detection of IN dimerization as well as for the identification of antiviral drugs targeting IN dimerization. Moreover, a FDA-approved proton-pump inhibitors, dexlansoprazole, was identified as a potential inhibitor for IN dimerization.
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, 100193, China.|Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou, 213001, China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Chongqing Center for Biomedicines and Medical Equipment, Chongqing Academy of Science and Technology, Chongqing, 401123, China.
authors.forename: Hongqiu
authors.initials: H
authors.lastname: He
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, 100193, China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Liu
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, 100193, China.
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Meng
authors.affiliation: Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing, 100193, China.
authors.forename: Shunxing
authors.initials: S
authors.lastname: Guo
mesh_terms: D019281:Dimerization; D017277:Drug Approval; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D019427:HIV Integrase / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D009532:Nickel / Q000737:chemistry; D012685:Sepharose / Q000737:chemistry; D014481:United States
chemical_list: D019428:HIV Integrase Inhibitors; D009532:Nickel; D012685:Sepharose; D019427:HIV Integrase