Illimaquinone, a selective inhibitor of the RNase H activity of human immunodeficiency virus type 1 reverse transcriptase.
01 Oct 1990-Antimicrobial Agents and Chemotherapy (American Society for Microbiology)-Vol. 34, Iss: 10, pp 2009-2012
TL;DR: Two synthetic derivatives of illimaquinone, in which the 6-hydroxyl group at the ortho position to one of carbonyl groups of the quinone ring was modified, proved ineffective in inhibiting the human immunodeficiency virus type 1 reverse transcriptase RNase H function, suggesting involvement of the 6'-hydroxym group in blocking the enzymatic activity.
Abstract: We studied the effect of the natural marine substance illimaquinone on the catalytic activities of reverse transcriptase from human immunodeficiency virus type 1. Illimaquinone inhibited the RNase H activity of the enzyme at concentrations of 5 to 10 microgram/ml, whereas RNA-dependent DNA polymerase and DNA-dependent DNA polymerase activities were considerably less susceptible to this inhibition. Two synthetic derivatives of illimaquinone, in which the 6'-hydroxyl group at the ortho position to one of carbonyl groups of the quinone ring was modified, proved ineffective in inhibiting the human immunodeficiency virus type 1 reverse transcriptase RNase H function, suggesting involvement of the 6'-hydroxyl group in blocking the enzymatic activity.
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TL;DR: A large variety of natural products have been described as anti-HIV agents, and for a portion thereof the target of interaction has been identified, and it is shown that L-c hicoric acid owes its anti-hIV activity to a specific interaction with the viral envelope gp120 rather than integrase.
Abstract: A large variety of natural products have been described as anti-HIV agents, and for a portion thereof the target of interaction has been identified. Cyanovirin-N, a 11-kDa protein from Cyanobacterium (blue-green alga) irreversibly inactivates HIV and also aborts cell-to-cell fusion and transmission of HIV, due to its high-affinity interaction with gp120. Various sulfated polysaccharides extracted from seaweeds (i.e., Nothogenia fastigiata, Aghardhiella tenera) inhibit the virus adsorption process. Ingenol derivatives may inhibit virus adsorption at least in part through down-regulation of CD4 molecules on the host cells. Inhibition of virus adsorption by flavanoids such as (-)epicatechin and its 3-O-gallate has been attributed to an irreversible interaction with gp120 (although these compounds are also known as reverse transcriptase inhibitors). For the triterpene glycyrrhizin (extracted from the licorice root Glycyrrhiza radix) the mode of anti-HIV action may at least in part be attributed to interference with virus-cell binding. The mannose-specific plant lectins from Galanthus, Hippeastrum, Narcissus, Epipac tis helleborine, and Listera ovata, and the N-acetylgl ucosamine-specific lectin from Urtica dioica would primarily be targeted at the virus-cell fusion process. Various other natural products seem to qualify as HIV-cell fusion inhibitors: the siamycins [siamycin I (BMY-29304), siamycin II (RP 71955, BMY 29303), and NP-06 (FR901724)] which are tricyclic 21-amino-acid peptides isolated from Streptomyces spp that differ from one another only at position 4 or 17 (valine or isoleucine in each case); the betulinic acid derivative RPR 103611, and the peptides tachyplesin and polyphemusin which are highly abundant in hemocyte debris of the horseshoe crabs Tachypleus tridentatus and Limulus polyphemus, i.e., the 18-amino-acid peptide T22 from which T134 has been derived. Both T22 and T134 have been shown to block T-tropic X4 HIV-1 strains through a specific antagonism with the HIV corecept or CXCR4. A number of natural products have been reported to interact with the reverse transcriptase, i.e., baicalin, avarol, avarone, psychotrine, phloroglucinol derivatives, and, in particular, calanolides (from the tropical rainforest tree, Calophyllum lanigerum) and inophyllums (from the Malaysian tree, Calophyllum inophyllum). The natural marine substance illimaquinone would be targeted at the RNase H function of the reverse transcriptase. Curcumin (diferuloylmethane, from turmeric, the roots/rhizomes of Curcuma spp), dicaffeoylquinic and dicaffeoylt artaric acids, L-chicoric acid, and a number of fungal metabolites (equisetin, phomasetin, oteromycin, and integric acid) have all been proposed as HIV-1 integrase inhibitors. Yet, we have recently shown that L-c hicoric acid owes its anti-HIV activity to a specific interaction with the viral envelope gp120 rather than integrase. A number of compounds would be able to inhibit HIV-1 gene expression at the transcription level: the flavonoid chrysin (through inhibition of casein kinase II, the antibacter ial peptides melittin (from bee venom) and cecropin, and EM2487, a novel substance produced by Streptomyces. (ABSTRACT TRUNCATED)
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TL;DR: Current knowledge, including the therapeutic potential, of these various inhibitors is discussed and in view of their potential clinical the utility, the problem of virus-drug resistance and possible strategies to circumvent this problem are addressed.
Abstract: Depending on the stage of their intervention with the viral replicative cycle, human immunodeficiency virus inhibitors could be divided into the following groups: (i) adsorption inhibitors (i.e., CD4 constructs, polysulfates, polysulfonates, polycarboxylates, and polyoxometalates), (ii) fusion inhibitors (i.e., plant lectins, succinylated or aconitylated albumins, and betulinic acid derivatives), (iii) uncoating inhibitors (i.e., bicyclams), (iv) reverse transcription inhibitors acting either competitively with the substrate binding site (i.e., dideoxynucleoside analogs and acyclic nucleoside phosphonates) or allosterically with a nonsubstrate binding site (i.e., non-nucleoside reverse transcriptase inhibitors), (v) integration inhibitors, (vi) DNA replication inhibitors, (vii) transcription inhibitors (i.e., antisense oligodeoxynucleotides and Tat antagonists), (viii) translation inhibitors (i.e., antisense oligodeoxynucleotides and ribozymes), (ix) maturation inhibitors (i.e., protease inhibitors, myristoylation inhibitors, and glycosylation inhibitors), and finally, (x) budding (assembly/release) inhibitors. Current knowledge, including the therapeutic potential, of these various inhibitors is discussed. In view of their potential clinical the utility, the problem of virus-drug resistance and possible strategies to circumvent this problem are also addressed.
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TL;DR: Deeper insights into the pathogenic mechanisms of disease, aggressive exploitation of those mechanisms for therapeutic gain, and continued commitment of both public and private sectors to support and collaborate in this research are needed.
Abstract: Since the discovery of human immunodeficiency virus (HIV) in 1983, significant progress has been made toward the discovery, development, and licensing of anti-HIV drugs. In vitro screens against whole virus are now being complemented by screens against specific viral targets, resulting in the development of clinical candidates acting at several critical stages of the viral life cycle. Despite these advances, clinical therapy remains largely palliative. In addition, it has recently been recognized that HIV resistance to most drugs may pose even greater obstacles. Moreover, emerging data on immunopathogenesis raise the possibility that even if virus was eliminated from an infected individual, the patient's immune system might not be capable of restoration to normal function. In the face of such obstacles, deeper insights into the pathogenic mechanisms of disease, aggressive exploitation of those mechanisms for therapeutic gain, and continued commitment of both public and private sectors to support and collaborate in this research are needed.
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01 Jan 2005
TL;DR: The problem of supply is a serious obstacle to the development of most terpenoid compounds with interesting pharmaceutical properties and cell culture and aquaculture will provide a solution for the supply issue of some valuable terpenes from terrestrial and marine environments, respectively.
Abstract: Terpenoids, also referred to as terpenes, are the largest group of natural compounds. Many terpenes have biological activities and are used for the treatment of human diseases. The worldwide sales of terpene-based pharmaceuticals in 2002 were approximately US $12 billion. Among these pharmaceuticals, the anticancer drug Taxol® and the antimalarial drug Artimesinin are two of the most renowned terpene-based drugs. All terpenoids are synthesized from two five-carbon building blocks. Based on the number of the building blocks, terpenoids are commonly classified as monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), and sesterterpenes (C25). These terpenoids display a wide range of biological activities against cancer, malaria, inflammation, and a variety of infectious diseases (viral and bacterial). In last two decades, natural-product bioprospecting from the marine environment has resulted in hundreds of terpenoids with novel structures and interesting bioactivities, with more to be discovered in the future. The problem of supply is a serious obstacle to the development of most terpenoid compounds with interesting pharmaceutical properties. Although total chemical synthesis plays a less important role in the production of some terpenoid drugs, it has contributed significantly to the development of terpenoid compounds and terpene-based drugs by providing critical information on structure-activity relationships (SAR) and chiral centers as well as generating analog libraries. Semisynthesis, on the other hand, has played a major role in the development and production of terpenoid-derived drugs. Metabolic engineering as an integrated bioengineering approach has made considerable progress to produce some terpenoids in plants and fermentable hosts. Cell culture and aquaculture will provide a solution for the supply issue of some valuable terpenes from terrestrial and marine environments, respectively. Recent advances in environmental genomics and other “-omics” technologies will facilitate isolation and discovery of new terpenoids from natural environments. There is no doubt that more terpenoid-based clinical drugs will become available and will play a more significant role in human disease treatment in the near future.
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References
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TL;DR: This review covers the literature published in 2014 for marine natural products, with 1116 citations referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms.
4,649 citations
TL;DR: The antiviral effects of a thymidine analogue,3'-azido-3'-deoxythymidine (BW A509U), which, as a triphosphate, inhibits the reverse transcriptase of HTLV-III/LAV, and the in vitro immune functions of normal T cells remain basically intact.
Abstract: The acquired immune deficiency syndrome (AIDS) is thought to result from infection of T cells by a pathogenic human retrovirus, human T-lymphotropic virus type III (HTLV-III) or lymphadenopathy-associated virus (LAV). In this report, we describe the antiviral effects of a thymidine analogue,3'-azido-3'-deoxythymidine (BW A509U), which, as a triphosphate, inhibits the reverse transcriptase of HTLV-III/LAV. This agent blocks the expression of the p24 gag protein of HTLV-III/LAV in H9 cells following exposure to virus. The drug also inhibits the cytopathic effect of HTLV-IIIB (a virus derived from a pool of American patients) and HTLV-III/RF-II (an isolate obtained from a Haitian patient that differs by about 20% in the amino acid sequence of the envelope gene from several isolates of HTLV-III/LAV, including HTLV-IIIB, analyzed so far). 3'-Azido-3'-deoxythymidine also completely blocks viral replication as assessed by reverse transcriptase production in normal human peripheral blood mononuclear cells exposed to HTLV-IIIB. Finally, at concentrations of 3'-azido-3'-deoxythymidine that block the in vitro infectivity and cytopathic effect of HTLV-IIIB, the in vitro immune functions of normal T cells remain basically intact.
1,782 citations
"Illimaquinone, a selective inhibito..." refers background in this paper
...Several compounds with diverse molecular structures, including various 2',3'-dideoxynucleosides (14, 21, 22) and 3'azidothymidine (9, 23, 35) that inhibit the viral RT in the form of 5'-triphosphates, foscarnet (28, 33), suramine (2, 7), rifabutin (1), and HPA 23 (26), have been shown to be active against HIV RT in vitro....
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TL;DR: In this paper, the capacity of purine and pyrimidine nucleoside derivatives to inhibit the infectivity and cytopathic effect of human T-lymphotropic virus type III in vitro was tested.
Abstract: Human T-lymphotropic virus type III (HTLV-III)/lymphadenopathy-associated virus (LAV) is a a newly discovered lymphotropic retrovirus that is cytopathic for helper/inducer T cells in vitro. This virus is the etiologic agent of the acquired immunodeficiency syndrome and related diseases. In the current study, we tested the capacity of purine and pyrimidine nucleoside derivatives to inhibit the infectivity and cytopathic effect of human T-lymphotropic virus type III in vitro. With the ribose moiety of the molecule in a 2',3'-dideoxy configuration, every purine (adenosine, guanosine, and inosine) and pyrimidine (cytidine and thymidine) nucleoside tested suppressed the virus, although the thymidine derivative seemed to have substantially less activity in our system than the others. In general, we observed essentially complete suppression of the virus at doses that were lower by a factor of 10 to 20 than those needed to inhibit the proliferation of the target T cells and the immune reactivity of normal T cells in vitro. An analysis of five adenosine congeners, which differed only in the sugar moiety, revealed that reduction (an absence of hydroxyl determinants) at both the 2' and 3' carbons of the ribose was necessary for an anti-viral effect, and an additional reduction at the 5' carbon nullified the anti-viral activity. These observations may be of value in developing a new class of experimental drugs for the therapy of human T-lymphotropic virus type III infections.
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"Illimaquinone, a selective inhibito..." refers background in this paper
...Several compounds with diverse molecular structures, including various 2',3'-dideoxynucleosides (14, 21, 22) and 3'azidothymidine (9, 23, 35) that inhibit the viral RT in the form of 5'-triphosphates, foscarnet (28, 33), suramine (2, 7), rifabutin (1), and HPA 23 (26), have been shown to be active against HIV RT in vitro....
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TL;DR: 4 dose regimens of 3'-azido-3'-deoxythymidine (AZT), a thymidine analogue with potent anti-viral activity against HTLV-III in vitro, were examined in 19 patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC).
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TL;DR: The retrovirus that causes AIDS has revealed enough of its life history for a variety of therapeutic strategies to be apparent that are suitable for immediate application in clinical trials or have already yielded positive results in some patients.
Abstract: The retrovirus that causes AIDS has revealed enough of its life history for a variety of therapeutic strategies to be apparent. Some of these are suitable for immediate application in clinical trials or have already yielded positive results in some patients.
470 citations
"Illimaquinone, a selective inhibito..." refers background in this paper
...Several compounds with diverse molecular structures, including various 2',3'-dideoxynucleosides (14, 21, 22) and 3'azidothymidine (9, 23, 35) that inhibit the viral RT in the form of 5'-triphosphates, foscarnet (28, 33), suramine (2, 7), rifabutin (1), and HPA 23 (26), have been shown to be active against HIV RT in vitro....
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