title: Potassium-dependent folding: a key to intracellular delivery of G-quartet oligonucleotides as HIV inhibitors.
abstract: Several groups have demonstrated that G-rich oligonucleotides forming G-quartet structures display activity as potential drugs, such as potent HIV inhibitors. The delivery of G-quartet oligonucleotides to their intracellular targets is a key obstacle to overcome for their clinical success. Here we have developed a novel system to deliver G-rich oligonucleotides into the cell nucleus, e.g., the site of HIV integration. On the basis of the property of potassium-induced formation of G-quartet structure, we explored the difference of K(+) concentrations inside (140 mM) and outside (4 mM) cells to induce the G-rich oligonucleotides to form different structures inside and outside cells. The key steps of this delivery system include the following: (i) First, the G-quartet structure is denatured to form a lipid-DNA complex, so that the molecules can be well delivered into cells. (ii) Then the delivered molecules are induced to form G-quartet structures by potassium inside cells since the G-quartet structure is the primary requirement for inhibition of HIV-1 HIV integrase (IN) activity. The molecules of a novel G-quartet HIV inhibitor, T40214, with the sequence of (GGGC)(4) were successfully delivered into the nuclei of target cells, which significantly decreased HIV-1 replication and increased the probability to target HIV-1 IN in infected cells.
authors.affiliation: Infectious Diseases Division, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA. njing@bcm.tmc.edu
authors.forename: Naijie
authors.initials: N
authors.lastname: Jing
authors.forename: Weijun
authors.initials: W
authors.lastname: Xiong
authors.forename: Yongli
authors.initials: Y
authors.lastname: Guan
authors.forename: Luke
authors.initials: L
authors.lastname: Pallansch
authors.forename: Shimei
authors.initials: S
authors.lastname: Wang
mesh_terms: D002460:Cell Line; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D006147:Guanine / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism*; D007700:Kinetics; D008081:Liposomes; D046911:Macromolecular Substances; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D010714:Phosphatidylethanolamines / Q000737:chemistry / Q000378:metabolism; D011188:Potassium / Q000737:chemistry*; D016662:Virus Integration / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D004337:Drug Carriers; D019428:HIV Integrase Inhibitors; D008081:Liposomes; D046911:Macromolecular Substances; D009838:Oligodeoxyribonucleotides; D010714:Phosphatidylethanolamines; D006147:Guanine; C020888:1,2-dielaidoylphosphatidylethanolamine; D004247:DNA; D011188:Potassium