Polycitone A, a novel and potent general inhibitor of retroviral reverse transcriptases and cellular DNA polymerases

Loya, Shoshana; Rudi, Amira; Kashman, Yoel; Hizi, Amnon

doi:10.1042/bj3440085

Cited by 43 publications

(11 citation statements)

References 45 publications

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“…Moreover, they are resolving an important issue of drug resistance generated because of synthetic drugs [9], e.g., a plant-derived product. Polycitone A is functional against the resistant strains of HIV [10]. Plant-derived products are also inexpensive and could be easily accessible in different parts of the world.…”

Section: Plant-derived Phytochemicals With Antiviral Effectsmentioning

confidence: 99%

Shikimic acid as intermediary model for the production of drugs effective against influenza virus

Singh

Gupta

Mishra

et al. 2020

Phytochemicals as Lead Compounds for New Drug Discovery

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Section: Plant-derived Phytochemicals With Antiviral Effectsmentioning

confidence: 99%

Shikimic acid as intermediary model for the production of drugs effective against influenza virus

Singh

Gupta

Mishra

et al. 2020

Phytochemicals as Lead Compounds for New Drug Discovery

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“…The RNase H function of RT, on the other hand, is hardly affected by this inhibitor. In this respect PAT resembles other natural compounds that were already found to be general inhibitors, namely toxiusol [13], 2-hexaprenylhydroquinone [15] and polycitone A [14]. PAT displays a similar paradigm of inhibition with cellular DNA polymerases from three different families, that is, calf thymus pol α from the α family (B family), pol β from the terminal transferase family and KF from the pol I family [28].…”

Section: Discussionmentioning

confidence: 70%

“…In our search for such compounds we have isolated two classes of RT inhibitors : (1) compounds with equal capacity to inhibit effectively both HIV-1 and HIV-2 RTs, but with poor or no ability to inhibit cellular DNA polymerases, and (2) compounds with a wide spectrum of inhibitory capacity against DNA polymerases with no specificity against RT. Toxiusol [13] and polycitone A [14] belong to the group of general inhibitors of DNA polymerases. They are capable of inhibiting DNA polymerization by blocking RT-DNA complex formation.…”

Section: Introductionmentioning

confidence: 99%

Mode of inhibition of HIV-1 reverse transcriptase by polyacetylenetriol, a novel inhibitor of RNA- and DNA-directed DNA polymerases

et al. 2002

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Polyacetylenetriol (PAT), a natural marine product from the Mediterranean sea sponge Petrosia sp., was found to be a novel general potent inhibitor of DNA polymerases. It inhibits equally well the RNA- and DNA-dependent DNA polymerase activities of retroviral reverse transcriptases (RTs) (i.e. of HIV, murine leukaemia virus and mouse mammary tumour virus) as well as cellular DNA polymerases (i.e. DNA polymerases alpha and beta and Escherichia coli polymerase I). A study of the mode and mechanism of the polymerase inhibition by PAT has been conducted with HIV-1 RT. PAT was shown to be a reversible non-competitive inhibitor. PAT binds RT independently and at a site different from that of the primer-template and dNTP substrates with high affinity (K(i)=0.51 microM and K(i)=0.53 microM with dTTP and with dGTP as the variable substrates respectively). Blocking the polar hydroxy groups of PAT has only a marginal effect on the inhibitory capacity, thus hydrophobic interactions are likely to play a major role in inhibiting RT. Preincubation of RT with the primer-template substrate prior to the interaction with PAT reduces substantially the inhibition capacity, probably by preventing these contacts. PAT does not interfere with the first step of polymerization, the binding of RT to DNA, nor does the inhibitor interfere with the binding of dNTP to RT/DNA complex, as evident from the steady-state kinetic study, whereby K(m) remains unchanged. We assume, therefore, that PAT interferes with subsequent catalytic steps of DNA polymerization. The inhibitor may alter the optimal stereochemistry of the polymerase active site relative to the primer terminus, bound dNTP and the metal ions that are crucial for efficient catalysis or, alternatively, may interfere with the thumb sub-domain movement and, thus, with the translocation of the primer-template following nucleotide incorporation.

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“…This compound inhibits the integrase terminal cleavage activity (IC 50 = 16 M) and strand transfer activity (IC 50 = 22 M) (Reddy et al, 1999). Polycitone A (Loya et al, 1999), an aromatic alkaloid isolated from the ascidian Polycitor sp. exhibits potent inhibitory impact on both RNA-(IC 50 = 245 ± 15 nM) and DNA-directed DNA polymerases (IC 50 = 470 ± 22 nM).…”

Section: Antivirals Derived From Miscellaneous Marine Organismsmentioning

confidence: 99%

“…exhibits potent inhibitory impact on both RNA-(IC 50 = 245 ± 15 nM) and DNA-directed DNA polymerases (IC 50 = 470 ± 22 nM). Polycitone A interferes with the DNA primer extension, as well as the formation of the RT-DNA complex (Loya et al, 1999).…”

Section: Antivirals Derived From Miscellaneous Marine Organismsmentioning

confidence: 99%

Marine compounds and their antiviral activities

2010

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Available treatments for many infectious diseases are limited. In particular, diseases caused by viral pathogens have demonstrated the need for new medicines, due to the increasing appearance of resistance to these available treatments. Thousands of novel compounds have been isolated from various marine organisms and tested for pharmacological properties, many of which are commercially available. The screening of natural products derived from marine species for antiviral activity has yielded a considerable number of active crude aqueous and organic solvent extracts. Today, over 40 compounds are commercially available in pharmacological markets, including alternative antiviral medicines or those being tested as potential antiviral drugs. Many more are being tested as potential antiviral drugs at the preclinical and clinical stages. The growing interest in marine-derived antiviral compounds, along with the development of new technology in marine cultures and extraction, will significantly expedite the current exploration of the marine environment for compounds with significant pharmacological applications, which will continue to be a promising strategy and new trend for modern medicine.

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Polycitone A, a novel and potent general inhibitor of retroviral reverse transcriptases and cellular DNA polymerases

Cited by 43 publications

References 45 publications

Shikimic acid as intermediary model for the production of drugs effective against influenza virus

Shikimic acid as intermediary model for the production of drugs effective against influenza virus

Mode of inhibition of HIV-1 reverse transcriptase by polyacetylenetriol, a novel inhibitor of RNA- and DNA-directed DNA polymerases

Marine compounds and their antiviral activities

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