title: Small molecule inhibitors targeting HIV-1 reverse transcriptase dimerization.
abstract: The enzymatic activities of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) are strictly correlated with the dimeric forms of this vital retroviral enzyme. Accordingly, the development of inhibitors targeting the dimerization of RT represents a promising alternative antiviral strategy. Based on mutational studies, we applied a structure-based ligand design approach generating pharmacophoric models of the large subunit connection subdomain to possibly identify small molecules from the ASINEX database, which might interfere with the RT subunit interaction. Docking studies of the selected compounds identified several candidates, which were initially tested in an in vitro subunit association assay. One of these molecules (MAS0) strongly reduced the association of the two RT subunits p51 and p66. Most notably, the compound simultaneously inhibited both the polymerase as well as the RNase H activity of the retroviral enzyme, following preincubation with t(1/2) of about 2 h, indicative of a slow isomerization step. This step most probably represents a shift of the RT dimer equilibrium from an active to an inactive conformation. Taken together, to the best of our knowledge, this study represents the first successful rational screen for a small molecule HIV RT dimerization inhibitor, which may serve as attractive hit compound for the development of novel therapeutic agents.
authors.affiliation: Institut für Molekulare Medizin, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
authors.forename: Dina
authors.initials: D
authors.lastname: Grohmann
authors.forename: Valentina
authors.initials: V
authors.lastname: Corradi
authors.forename: Mira
authors.initials: M
authors.lastname: Elbasyouny
authors.forename: Annika
authors.initials: A
authors.lastname: Baude
authors.forename: Florian
authors.initials: F
authors.lastname: Horenkamp
authors.forename: Sandra D
authors.initials: SD
authors.lastname: Laufer
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.forename: Tobias
authors.initials: T
authors.lastname: Restle
mesh_terms: D018360:Crystallography, X-Ray; D019281:Dimerization; D015195:Drug Design; D004795:Enzyme Stability / Q000187:drug effects; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology*; D008024:Ligands; D009154:Mutation; D011485:Protein Binding / Q000187:drug effects; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D054309:Ribonuclease H, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D008024:Ligands; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D054309:Ribonuclease H, Human Immunodeficiency Virus