title: Pharmacokinetic analysis of polyamide nucleic-acid-cell penetrating peptide conjugates targeted against HIV-1 transactivation response element.
abstract: We have demonstrated that polyamide nucleic acids complementary to the transactivation response (TAR) element of HIV-1 LTR inhibit HIV-1 production when transfected in HIV-1 infected cells. We have further shown that anti-TAR PNA (PNA(TAR)) conjugated with cell-penetrating peptide (CPP) is rapidly taken up by cells and exhibits strong antiviral and anti-HIV-1 virucidal activities. Here, we pharmacokinetically analyzed (125)I-labeled PNA(TAR) conjugated with two CPPs: a 16-mer penetratin derived from antennapedia and a 13-mer Tat peptide derived from HIV-1 Tat. We administered the (125)I-labeled PNA(TAR)-CPP conjugates to male Balb/C mice through intraperitoneal or gavage routes. The naked (125)I-labeled PNA(TAR) was used as a control. Following a single administration of the labeled compounds, their distribution and retention in various organs were monitored at various time points. Regardless of the administration route, a significant accumulation of each PNA(TAR)-CPP conjugate was found in different mouse organs and tissues. The clearance profile of the accumulated radioactivity from different organs displayed a biphasic exponential pathway whereby part of the radioactivity cleared rapidly, but a significant portion of it was slowly released over a prolonged period. The kinetics of clearance of individual PNA(TAR)-CPP conjugates slightly varied in different organs, while the overall biphasic clearance pattern remained unaltered regardless of the administration route. Surprisingly, unconjugated naked PNA(TAR) displayed a similar distribution and clearance profile in most organs studied although extent of its uptake was lower than the PNA(TAR)-CPP conjugates.
authors: Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, Newark, New Jersey, USA.
authors: Sabyasachi
authors: S
authors: Ganguly
authors: Binay
authors: B
authors: Chaubey
authors: Snehlata
authors: S
authors: Tripathi
authors: Alok
authors: A
authors: Upadhyay
authors: Prasad V S V
authors: PV
authors: Neti
authors: Roger W
authors: RW
authors: Howell
authors: Virendra Nath
authors: VN
authors: Pandey
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D057846:Cell-Penetrating Peptides; D016325:HIV Long Terminal Repeat / Q000187:drug effects*; D015497:HIV-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009696:Nucleic Acids / Q000378:metabolism; D009757:Nylons / Q000378:metabolism; D020135:Peptide Nucleic Acids / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics; D010455:Peptides / Q000138:chemical synthesis / Q000378:metabolism*; D020218:Response Elements / Q000187:drug effects*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D019380:Anti-HIV Agents; D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D009696:Nucleic Acids; D009757:Nylons; D020135:Peptide Nucleic Acids; D010455:Peptides; D054322:tat Gene Products, Human Immunodeficiency Virus; C414409:penetratin