title: Alizarine derivatives as new dual inhibitors of the HIV-1 reverse transcriptase-associated DNA polymerase and RNase H activities effective also on the RNase H activity of non-nucleoside resistant reverse transcriptases.
abstract: HIV-1 reverse transcriptase (RT) has two associated activities, DNA polymerase and RNase H, both essential for viral replication and validated drug targets. Although all RT inhibitors approved for therapy target DNA polymerase activity, the search for new RT inhibitors that target the RNase H function and are possibly active on RTs resistant to the known non-nucleoside inhibitors (NNRTI) is a viable approach for anti-HIV drug development. In this study, several alizarine derivatives were synthesized and tested for both HIV-1 RT-associated activities. Alizarine analogues K-49 and KNA-53 showed IC(50) values for both RT-associated functions of ∼ 10 μm. When tested on the K103N RT, both derivatives inhibited the RT-associated functions equally, whereas when tested on the Y181C RT, KNA-53 inhibited the RNase H function and was inactive on the polymerase function. Mechanism of action studies showed that these derivatives do not intercalate into DNA and do not chelate the divalent cofactor Mg(2+) . Kinetic studies demonstrated that they are noncompetitive inhibitors, they do not bind to the RNase H active site or to the classical NNRTI binding pocket, even though efavirenz binding negatively influenced K-49/KNA-53 binding and vice versa. This behavior suggested that the alizarine derivatives binding site might be close to the NNRTI binding pocket. Docking experiments and molecular dynamic simulation confirmed the experimental data and the ability of these compounds to occupy a binding pocket close to the NNRTI site.
authors.affiliation: Department of Applied Sciences in Biosystems, University of Cagliari, Cagliari, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Esposito
authors.forename: Tatyana
authors.initials: T
authors.lastname: Kharlamova
authors.forename: Simona
authors.initials: S
authors.lastname: Distinto
authors.forename: Luca
authors.initials: L
authors.lastname: Zinzula
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Cheng
authors.forename: Ginger
authors.initials: G
authors.lastname: Dutschman
authors.forename: Giovanni
authors.initials: G
authors.lastname: Floris
authors.forename: Patrick
authors.initials: P
authors.lastname: Markt
authors.forename: Angela
authors.initials: A
authors.lastname: Corona
authors.forename: Enzo
authors.initials: E
authors.lastname: Tramontano
mesh_terms: D000880:Anthraquinones / Q000494:pharmacology*; D001483:Base Sequence; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D016296:Mutagenesis; D019384:Nucleic Acid Synthesis Inhibitors; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D016914:Ribonuclease H / Q000037:antagonists & inhibitors*
chemical_list: D000880:Anthraquinones; D019384:Nucleic Acid Synthesis Inhibitors; D018894:Reverse Transcriptase Inhibitors; C010078:alizarin; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D016914:Ribonuclease H