Current lead natural products for the chemotherapy of human immunodeficiency virus (HIV) infection

Clercq, Erik De

doi:10.1002/1098-1128(200009)20:5<323::aid-med1>3.0.co;2-a

Cited by 316 publications

(184 citation statements)

References 87 publications

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“…It has been used as a model peptide for various purposes over the last decades (for a general review, see 16 ), and has shown therapeutic potential with antimicrobial, anti-inflammatory [17][18][19][20] , antiparasitic 21 , and anticancer [22][23] activity, as well as for treatment 24 and prevention 25 of HIV. Like many CAPs, melittin binds to membranes as an amphipathic α-helix [26][27][28] .…”

Section: Introductionmentioning

confidence: 99%

Role of the Cationic C-Terminal Segment of Melittin on Membrane Fragmentation

2016

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The widespread distribution of cationic antimicrobial peptides capable of membrane fragmentation in nature underlines their importance to living organisms. In the present work, we determined the impact of the electrostatic interactions associated with the cationic Cterminal segment of melittin, a 26-amino acid peptide from bee venom (net charge +6), on its binding to model membranes and on the resulting fragmentation. In order to detail the role played by the C-terminal charges, we prepared a melittin analogue for which the 4 cationic amino acids in positions 21 to 24 were substituted with the polar residue citrulline, providing a peptide with the same length and amphiphilicity but with a lower net charge (+2). We compared the peptide bilayer affinity and the membrane fragmentation for bilayers prepared from dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine (DPPS) mixtures. It is shown that neutralization of the C-terminal considerably increased melittin affinity for zwitterionic membranes. The unfavorable contribution associated with transferring the cationic C-terminal in a less polar environment was reduced, leaving the hydrophobic interactions, which drive the peptide insertion in bilayers, with limited counterbalancing interactions. The presence of negatively charged lipids (DPPS) in bilayers increased melittin binding by introducing attractive electrostatic interactions, the augmentation being, as expected, greater for native melittin than for its citrullinated analogue. The membrane fragmentation power of the peptide was shown to be controlled by electrostatic interactions and could be modulated by the charge carried by both the membrane and the lytic peptide. The analysis of the lipid composition of the extracted fragments from DPPC/DPPS bilayers revealed no lipid specificity. It is proposed that extended phase separations are more susceptible to lead to the extraction of a lipid species in a specific manner than a specific lipid-peptide affinity. The present work on the lipid extraction by melittin and citrullinated melittin with model membranes emphasizes the complex relation between the affinity, the lipid extraction/membrane fragmentation, and the lipid specificity.

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Section: Introductionmentioning

confidence: 99%

Role of the Cationic C-Terminal Segment of Melittin on Membrane Fragmentation

2016

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“…It has long been recognised that natural products, especially those derived from plants, are excellent sources of new anti-HIV-1 drugs (De Clercq, 2000, 2005Esimone et al, 2009Esimone et al, , 2010Esimone et al, , 2012. Some of these plantsderived antiretroviral therapies have been shown to have inhibitory activities against several HIV-1 processes, including viral entry, reverse transcription, replication, integration, virus maturation and virion budding.…”

Section: Discussionmentioning

confidence: 99%

Extracts of Moringa oleifera Lam. showing inhibitory activity against early steps in the infectivity of HIV-1 lentiviral particles in a viral vector-based screening

Nworu¹,

C²,

Okoye³

et al. 2013

Afr. J. Biotechnol.

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“…variety of natural products have been described as anti-HIV agents (22), such as ingenol derivatives (23), betulinic acid and its derivatives (24,25), and hypericin (26,27). On the contrary, few natural inhibitors against plant-infecting viruses were reported except the anti-TMV agent pyrroloisoquinoline alkaloids (28).…”

Section: Discussionmentioning

confidence: 99%

Seco -pregnane steroids target the subgenomic RNA of alphavirus-like RNA viruses

Wang²,

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Plants have evolved multiple mechanisms to selectively suppress pathogens by production of secondary metabolites with antimicrobial activities. Therefore, direct selections for antiviral compounds from plants can be used to identify new agents with potent antiviral activity but not toxic to hosts. Here, we provide evidence that a class of compounds, seco-pregnane steroid glaucogenin C and its monosugar-glycoside cynatratoside A of Strobilanthes cusia and three new pantasugar-glycosides of glaucogenin C of Cynanchum paniculatum, are effective and selective inhibitors to alphavirus-like positive-strand RNA viruses including plant-infecting tobacco mosaic virus (TMV) and animal-infecting Sindbis virus (SINV), eastern equine encephalitis virus, and Getah virus, but not to other RNA or DNA viruses, yet they were not toxic to host cells. In vivo administration of the compounds protected BALB/c mice from lethal SINV infection without adverse effects on the mice. Using TMV and SINV as models, studies on the action mechanism revealed that the compounds predominantly suppress the expression of viral subgenomic RNA(s) without affecting the accumulation of viral genomic RNA. Our work suggested that the viral subgenomic RNA could be a new target for the discovery of antiviral drugs, and that seco-pregnane steroid and its four glycosides found in the two medicinal herbs have the potential for further development as antiviral agents against alphavirus-like positive-strand RNA viruses.antiviral drugs ͉ Strobilanthes cusia ͉ Cynanchum atratum V iruses replicate in host cells by hijacking the host-cell metabolic machinery. It is therefore difficult for antiviral therapies to inhibit only viral functions but spare host cellular processes. Nevertheless, great progress has been achieved over the past decades in antiviral research and therapy to reduce morbidity and mortality in virus-infected individuals (1, 2), and many antiviral drugs have been approved in recent years, most of which targeted either viral proteins or host cellular proteins. However, some of these compounds might induce the resistance of viruses to them and cause cell toxicity (3-5). The continuing emergence of highly pathogenic viruses like avian influenza viruses and severe acute respiratory syndrome coronavirus underscores the importance of advancing the search for effective antiviral agents. Plants have evolved constitutive and inducible defense mechanisms by producing a vast array of secondary metabolites against various microbial pathogens (6). Many herbaceous plants have been used in traditional Chinese medicine to treat viral diseases (7). It is conceivable that antiviral compounds would occur in plants as part of their innate defense arsenal, and the vast assortment of secondary metabolites could serve as a large pool for screening for previously undescribed antiviral compounds with a selective target spectrum and nontoxic to the host plants. Here, we provide evidence that a class of compounds, the seco-pregnane steroid and its glycosides from Strobilanthe...

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Current lead natural products for the chemotherapy of human immunodeficiency virus (HIV) infection

Cited by 316 publications

References 87 publications

Role of the Cationic C-Terminal Segment of Melittin on Membrane Fragmentation

Role of the Cationic C-Terminal Segment of Melittin on Membrane Fragmentation

Extracts of Moringa oleifera Lam. showing inhibitory activity against early steps in the infectivity of HIV-1 lentiviral particles in a viral vector-based screening

Seco -pregnane steroids target the subgenomic RNA of alphavirus-like RNA viruses

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