Abstract:
:The transactivator responsive region (TAR) present in the 5'-NTR of the HIV-1 genome represents a potential target for antiretroviral intervention and a model system for the development of specific inhibitors of RNA-protein interaction. Earlier, we have shown that an anti-TAR polyamide nucleotide analog (PNA(TAR)) conjugated to a membrane transducing (MTD) peptide, transportan, is efficiently taken up by the cells and displays potent antiviral and virucidal activity [B. Chaubey, S. Tripathi, S. Ganguly, D. Harris, R. A. Casale and V. N. Pandey (2005) Virology, 331, 418-428]. In the present communication, we have conjugated five different MTD peptides, penetratin, tat peptide, transportan-27, and two of its truncated derivatives, transportan-21 and transportan-22, to a 16mer PNA targeted to the TAR region of the HIV-1 genome. The individual conjugates were examined for their uptake efficiency as judged by FACScan analysis, uptake kinetics using radiolabeled conjugate, virucidal activity and antiviral efficacy assessed by inhibition of HIV-1 infection/replication. While FACScan analysis revealed concentration-dependent cellular uptake of all the PNA(TAR)-peptide conjugates where uptake of the PNA(TAR)-penetratin conjugate was most efficient as >90% MTD was observed within 1 min at a concentration of 200 nM. The conjugates with penetratin, transportan-21 and tat-peptides were most effective as an anti-HIV virucidal agents with IC50 values in the range of 28-37 nM while IC50 for inhibition of HIV-1 replication was lowest with PNA(TAR)-transportan-27 (0.4 microM) followed by PNA(TAR)-tat (0.72 microM) and PNA(TAR)-penetratin (0.8 microM). These results indicate that anti-HIV-1 PNA conjugated with MTD peptides are not only inhibitory to HIV-1 replication in vitro but are also potent virucidal agents which render HIV-1 virions non-infectious upon brief exposure.
journal_name
Nucleic Acids Resjournal_title
Nucleic acids researchauthors
Tripathi S,Chaubey B,Ganguly S,Harris D,Casale RA,Pandey VNdoi
10.1093/nar/gki743keywords:
subject
Has Abstractpub_date
2005-08-02 00:00:00pages
4345-56issue
13eissn
0305-1048issn
1362-4962pii
33/13/4345journal_volume
33pub_type
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