title: Methylene bisphosphonates as the inhibitors of HIV RT phosphorolytic activity.
abstract: The structure-function analysis of 36 methylenebisphosphonates (BPs) as inhibitors of the phosphorolytic activity of native and drug-resistant forms of HIV-1 reverse transcriptase (RT) was performed. It was shown that with the increase of the inhibitory potential of BPs towards the phosphorolytic activity raises their ability to inhibit the RT-catalyzed DNA elongation. Herein, we report the impact of the thymidine analog mutations (TAM) on the activity of bisphosphonates, as well as some structural features of the BPs, allowing them to maintain the inhibitory activity on the enzyme resistant to nucleoside analog therapy. We estimated the Mg(2+)-coordinating group structure, the linker and the aromatic pharmacophore influence on the inhibitory potential of the BPs. Based on the 31 BPs SAR, several BPs with improved inhibitory properties were designed and synthesized.
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova st.-32, Moscow, Russia. Electronic address: JDmitry@hotmail.com.
authors.forename: D V
authors.initials: DV
authors.lastname: Yanvarev
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova st.-32, Moscow, Russia.
authors.forename: A N
authors.initials: AN
authors.lastname: Korovina
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova st.-32, Moscow, Russia.
authors.forename: N N
authors.initials: NN
authors.lastname: Usanov
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova st.-32, Moscow, Russia.
authors.forename: O A
authors.initials: OA
authors.lastname: Khomich
authors.affiliation: School of Pharmacy, Biocenter Kuopio, University of Eastern Finland, Kuopio, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Vepsäläinen
authors.affiliation: School of Pharmacy, Biocenter Kuopio, University of Eastern Finland, Kuopio, Finland.
authors.forename: E
authors.initials: E
authors.lastname: Puljula
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova st.-32, Moscow, Russia.
authors.forename: M K
authors.initials: MK
authors.lastname: Kukhanova
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova st.-32, Moscow, Russia.
authors.forename: S N
authors.initials: SN
authors.lastname: Kochetkov
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000201:enzymology*; D008274:Magnesium / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D009690:Nucleic Acid Conformation; D010766:Phosphorylation / Q000187:drug effects; D011487:Protein Conformation; D012367:RNA, Viral / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004164:Diphosphonates; D012367:RNA, Viral; C027474:methylene diphosphonate; D000255:Adenosine Triphosphate; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D004259:DNA-Directed DNA Polymerase; D008274:Magnesium
keywords: Bisphosphonates; Excision; HIV; Pyrophosphorolysis; Resistance; Reverse transcriptase; SAR; TAM