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Single-stranded DNA aptamer RT1t49 inhibits RT polymerase and RNase H functions of HIV type 1, HIV type 2, and SIVCPZ RTs.
- Source :
-
AIDS research and human retroviruses [AIDS Res Hum Retroviruses] 2007 May; Vol. 23 (5), pp. 699-708. - Publication Year :
- 2007
-
Abstract
- Natural and selected resistance of HIV-1 to current anti-HIV drugs continues to pose serious problems to the development of HIV-1 antivirals. The viral reverse transcriptase (RT) is a proven therapeutic target. Single-stranded RNA and DNA (ssRNA and ssDNA) aptamers have been selected that specifically and potently inhibit RT function. In particular, the ssDNA aptamer RT1t49 was previously selected to recognize the RT from a subtype B strain of HIV-1 and binds with a reported K(d) of 4 nM. In the present work, we show that RT1t49 inhibits recombinant RT cloned from diverse branches of the primate lentiviral family. Aptamer concentrations required for half-maximal inhibition of all HIV-1, HIV-2, and SIV(CPZ) RTs assayed were in the low-to mid-nanomolar range for both polymerase and RNase H activities. Using pre-steady-state and order-of-addition kinetic analyses, we also established that this ssDNA aptamer competes with primer-template for access to RT, and that addition of a nucleoside analog RT inhibitor (NRTI) to the in vitro reaction enhanced the overall effectiveness of both drugs, while nonnucleoside analog RT inhibitors (NNRTIs) exhibited simple additivity. This is the first demonstration of universal inhibition of HIV and SIV(cpz) RTs by a nucleic acid aptamer and supports previous reports suggesting that resistance to RT1t49 may be exceptionally infrequent.
- Subjects :
- Animals
Aptamers, Nucleotide genetics
DNA, Single-Stranded genetics
HIV Reverse Transcriptase antagonists & inhibitors
Humans
RNA-Directed DNA Polymerase metabolism
Ribonuclease H antagonists & inhibitors
Aptamers, Nucleotide pharmacology
DNA, Single-Stranded pharmacology
HIV-1 enzymology
HIV-2 enzymology
Reverse Transcriptase Inhibitors pharmacology
Simian Immunodeficiency Virus enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 0889-2229
- Volume :
- 23
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- AIDS research and human retroviruses
- Publication Type :
- Academic Journal
- Accession number :
- 17530996
- Full Text :
- https://doi.org/10.1089/aid.2006.0262