Biosensor-based kinetic characterization of the interaction between HIV-1 reverse transcriptase and non-nucleoside inhibitors

Geitmann, MatthisUppsala universitet,Institutionen för biokemi och organisk kemi (author)

Details of the interaction between HIV-1 reverse transcriptase and non-nucleoside inhibitors (NNRTIs) have been elucidated using a biosensor-based approach. This initial study was performed with HIV-1 reverse transcriptase mutant K103N, the phenethylthioazolylthiourea compound (PETT) MIV-150, and the three NNRTIs licensed for clinical use: nevirapine, delavirdine, and efavirenz. Mathematical evaluation of the experimental data with several interaction models revealed that the four inhibitors interacted with HIV-1 RT with varying degrees of complexity. The simplest adequate model accounted for two different conformations of the free enzyme, of which only one can bind the inhibitor, consistent with a previously hypothesized population-shift model including a preformation of the NNRTI binding site. In addition, a heterogeneous binding was observed for delavirdine, efavirenz, and MIV-150, indicating that two noncompetitive and kinetically distinct enzyme-inhibitor complexes could be formed. Furthermore, for these compounds, there were indications for ligand-induced conformational changes.

NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
Binding Sites
Biosensing Techniques/*methods
Delavirdine/chemistry/pharmacology
Enzyme Activation/drug effects
HIV-1 Reverse Transcriptase/*antagonists & inhibitors/chemistry
Kinetics
Molecular Structure
Nevirapine/chemistry/pharmacology
Oxazines/chemistry/pharmacology
Protein Conformation
Pyridines/chemistry/pharmacology
Reverse Transcriptase Inhibitors/chemistry/*pharmacology
Structure-Activity Relationship
Time Factors
Urea/analogs & derivatives/chemistry/pharmacology
Cell and molecular biology
Cell- och molekylärbiologi

Unge, TorstenUppsala universitet,Strukturell molekylärbiologi (author)
Danielson, U. HelenaUppsala universitet,Institutionen för biokemi och organisk kemi(Swepub:uu)helenads (author)
Uppsala universitetInstitutionen för biokemi och organisk kemi (creator_code:org_t)

In:Journal of Medicinal Chemistry: American Chemical Society (ACS)49:8, s. 2367-740022-26231520-4804

By the author/editor: Geitmann, Matthi ...; Unge, Torsten; Danielson, U. He ...

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

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