Antiviral activity of diterpenes isolated from the Brazilian marine alga Dictyota menstrualis against human immunodeficiency virus type 1 (HIV-1)
Introduction
The acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV), has become a serious threat to global public health in the last decades. The first generation drugs, such as AZT, ddC, ddI and D4T (Huang et al., 1992, Sergheraert et al., 1993) have been extensively used in the clinic, but the rapid development of virus resistance to these nucleoside analogs represents a significant obstacle to anti-HIV therapy (Biesert et al., 1991, St. Clair et al., 1991, Najera et al., 1994, Menendez-Arias, 2002). Furthermore, these drugs have limited or transient benefits due to their adverse side effects (Tozser, 2001). In the light of these considerations, new classes of drugs that can supplement, or partially replace, existing drugs are definitely needed for a suitable long-term use.
The discovery and characterization of new anti-HIV agents with novel structures or mechanism(s) of action and low toxicity to the host remain priority (Barreca et al., 2003). Specific inhibitors of several steps of the viral replicative cycle, including viral attachment and entry, reverse transcription, provirus DNA integration and RNA packaging, have been subjected to preclinical investigation or have already entered clinical trials. A considerable number of these inhibitors have been isolated from natural sources, such as marine algae and plants (De Clercq, 2000, Jung et al., 2000).
In this work, the inhibitory activity of the Brazilian marine alga Dictyota menstrualis on HIV-1 replication was investigated. Two diterpenes were isolated from the alga extract as the biologically active compounds and the viral molecular target for both compounds was determined.
Section snippets
Samples
Fractionation of the alga D. menstrualis, purification and chemical characterization of the (6R)-6-hydroxydichotoma-3,14-diene-1,17-dial and its natural acetate-derivative (6R)-6-acetoxi-dichotoma-3,14-diene-1,17-dial, named here as Da-1 and AcDa-1 (Scheme 1) were previously described (Teixeira et al., 2001). Briefly, the brownish residue (CH2Cl2/MeOH fraction) obtained after extraction from the fresh alga was partitioned between n-hexane (n-hexane fraction 1) and MeOH. The n-hexane fraction 1
Inhibition of HIV-1 replication in PM-1 cells by isolated fractions and purified diterpenes obtained from the extract of the alga D. menstrualis
To evaluate the antiviral potential of the marine alga D. menstrualis, PM-1 cells were infected with HIV-1 subtype B isolate BR48 in the presence of increasing concentrations of the CH2Cl2/MeOH fraction of the alga extract and at 7 days post-infection virion production was quantified. A dose-dependent inhibition of virus replication was observed (Fig. 1). To find out the substance that could account for the antiviral activity of the CH2Cl2/MeOH fraction of the alga extract, it was further
Discussion
The search for new classes of antiretroviral drugs has become imperative if we consider the numerous reports on the long-term toxicity to the host and the acquired resistance to the currently available drugs for anti-HIV therapy (Lucas et al., 1999, Menendez-Arias, 2002). The number of natural products with antiviral activity derived from microorganisms, plants, marine invertebrates and particularly algae has increased in the last decade (Cardellina et al., 1993, Loya et al., 1994, Loya et al.,
Acknowledgements
This work was supported by grants from CNPq and FAPERJ. Fellowship granted to Pereira H.S. from CNPq (Brasil) is gratefully acknowledged.
References (30)
- et al.
Anti-HIV agents: design and discovery of new potent RT inhibitors
IL Farmaco.
(2003) - et al.
Single-step purification of recombinant wild-type and mutant HIV-1 reverse transcriptase
Protein Expr. Purif.
(1996) - et al.
Selective action of 2′,3′-didehydro-2′,3′-dideoxythymidine triphosphate on human immunodeficiency virus reverse transcriptase and human DNA polymerases
J. Biol. Chem.
(1992) - et al.
3,5,8-Trihydroxy-4-quinolone, a novel natural inhibitor of the reverse transcriptases of human immunodeficiency viruses type 1 and type 2
Arch. Biochem. Biophys.
(1994) Targeting HIV: antiretroviral therapy and development of drug resistance
Trends Pharmacol. Sci.
(2002)- et al.
Chemotaxonomic study of the diterpenes from the brown alga Dictyota menstrualis
Biochem. Syst. Ecol.
(2001) - et al.
Structural biology of HIV
J. Mol. Biol.
(1999) - et al.
Nef stimulates human immunodeficiency virus type 1 proviral DNA synthesis
J. Virol.
(1995) - et al.
Biochemical and genetical analysis of AZT-resistant HIV-mutants
Behring Inst. Mitt.
(1991) - et al.
A chemical screening strategy for the dereplication and prioritization of HIV-inhibitory aqueous natural products extracts
J. Nat. Prod.
(1993)