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.
Highlights
Retroviruses such as Human immunodeficiency virus (HIV)-1 are characterized by integration of reverse-transcribed viral genome into the host cell chromosome[1]
Incubation at room temperature allows the formation of GST-tagged IN protein (GST-IN)/His6-IN heterodimers as well as GST-IN and His6-IN homodimers
Heterodimers will be captured by Ni2+ -coated magnetic beads through C-terminal His6-tag and detected by alkaline phosphatase conjugated anti-GST antibody through its N-terminal GST-tag
Summary
Retroviruses such as HIV-1 are characterized by integration of reverse-transcribed viral genome into the host cell chromosome[1]. As a critical enzyme in the viral life cycle, IN is currently targeted by three FDA-approved drugs: raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG)[3]. All these drugs have the same mechanism of action: blocking the strand transfer activity of IN and are collectively termed as IN strand transfer inhibitors (INSTIs). An AlphaScreen technology-based method for screening IN dimerization inhibitor was reported. This method has an obvious limitation: the requirement of expensive and sophisticated instruments which are not available to all laboratories. Shorter development times and higher success rates, drug repositioning is ideally suited for academia-based drug discovery[14]
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