MIV-170: A novel NNRTI exhibiting tight binding to HIV-1 reverse transcriptase (RT)

MIV-170 : A novel NNRTI exhibiting tight binding to HIV-1 reverse transcriptase (RT)

Elinder, Malin (author): Uppsala universitet,Institutionen för biokemi och organisk kemi

Danielson, Helena (author): Uppsala universitet,Institutionen för biokemi och organisk kemi

Unge, Torsten (author): Uppsala universitet,Institutionen för cell- och molekylärbiologi

VanHam, Guido (author)

Öberg, Bo (author)

(creator_code:org_t)

Related links:: https://urn.kb.se/re...; show more...; https://doi.org/10.1...; show less...

Abstract Subject headings

The NNRTI MIV-170 has been found to be a very efficient inhibitor of wtHIV and HIV mutant strains resistant to the NNRTIs used in the clinic. To better understand the interaction between MIV-170 and HIV-1 the details of this have been studied by different methods. The kinetics of the interaction between MIV-170 and HIV-1 RT was analysed using a biosensor assay. The association and dissociation rates were determined using immobilized wtRT or RT mutants and MIV-170 as analyte. The results demonstrated that MIV-170 had both a faster association and a slower dissociation rate than efavirenz, nevirapine and delavirdine, thus exhibiting a higher affinity than these compounds. The strength of the interaction between the NNRTIs and RT and RT mutants in the biosensor assay was compared to the reversibility of inhibition in cell culture experiments. In these experiments virus and infected cells were incubated with MIV-170 and other NNRTIs for various times and after removal of the compounds the remaining infectivity was assayed. X-ray analysis of the binding of MIV-170 to HIV-1 RT displayed extensive interactions, not only between the compound and the lining amino acids but also between these residues, turning the binding cavity into a rigid entity and explaining the tight binding in the biosensor assay and the inactivation of HIV.

By the author/editor: Elinder, Malin; Danielson, Helen ...; Unge, Torsten; VanHam, Guido; Öberg, Bo

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