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1.
J Virol ; 94(15)2020 07 16.
Article in English | MEDLINE | ID: mdl-32461309

ABSTRACT

Oregano essential oil has long been known for its health-promoting benefits. Here, we report its activity against viral replication. Oregano oil was found to specifically inhibit lentiviruses, such as human and simian immunodeficiency viruses (HIV and SIV), irrespective of virus tropism, but not hepatitis C virus, adenovirus 5 (ADV5), Zika virus, and influenza (H1N1) virus. Oregano oil's most abundant components, carvacrol and its isomer, thymol, were shown to block virus-target cell fusion while not perturbing other stages of the virus life cycle. We detected changes in virus particle density, suggesting that cholesterol depletion from the HIV-1 envelope membrane reduces virus entry. Furthermore, infection was rescued by adding exogenous cholesterol. The evolution of viral resistance to carvacrol supported this mechanism of action with the identification of mutations in the viral gp41 fusion protein that counteracted cholesterol depletion. In addition, resistance to carvacrol emerged later than typically observed for other clinically used drugs, strengthening its antiviral potential. Structure-activity relationship studies revealed key motifs of carvacrol and thymol required for HIV neutralization and identified previously unknown active analogs. Carvacrol was also shown to additively cooperate with antiretroviral therapy. In sum, oregano oil and improved carvacrol and thymol analogs could be considered to supplement current HIV therapeutics.IMPORTANCE Oregano essential oil has multiple benefits in traditional medicine, cosmetics, and food industries. Carvacrol and its analog, thymol, are well-described components of oregano oil. Here, we show that these compounds inhibit HIV-target cell fusion independently of viral tropism. Our results suggest that carvacrol and thymol alter the cholesterol content of the viral membrane, blocking HIV-1 entry into the target cell. Resistance to carvacrol has selected for viruses with mutations in the viral envelope glycoprotein, gp41. This protein is known for its interaction with cholesterol present in membrane lipid rafts. Together, these results demonstrate the potential of therapies targeting the viral envelope membrane, and oregano oil is a safe supplement to antiretrovirals, potentially delaying disease progression and resistance development.


Subject(s)
Cymenes/pharmacology , HIV Envelope Protein gp41/metabolism , HIV-1/metabolism , Origanum/chemistry , Plant Oils/pharmacology , Virus Internalization/drug effects , Animals , Cholesterol/genetics , Cholesterol/metabolism , Cymenes/chemistry , Drug Resistance, Viral , HIV Envelope Protein gp41/genetics , HIV Infections/drug therapy , HIV Infections/genetics , HIV Infections/metabolism , HIV-1/genetics , HeLa Cells , Humans , Macaca mulatta , Mutation , Plant Oils/chemistry
2.
Infect Immun ; 67(8): 4072-83, 1999 Aug.
Article in English | MEDLINE | ID: mdl-10417176

ABSTRACT

The recent discovery that the Treponema pallidum genome encodes 12 orthologs of the Treponema denticola major sheath protein (Msp) prompted us to reexamine the cellular location and topology of the T. denticola polypeptide. Experiments initially were conducted to ascertain whether Msp forms an array on or within the T. denticola outer membrane. Transmission electron microscopy (EM) of negatively stained and ultrathin-sectioned organisms failed to identify a typical surface layer, whereas freeze-fracture EM revealed that the T. denticola outer membrane contains heterogeneous transmembrane proteins but no array. In contrast, a lattice-like structure was observed in vesicles released from mildly sonicated treponemes; combined EM and biochemical analyses demonstrated that this structure was the peptidoglycan sacculus. Immunoelectron microscopy (IEM) subsequently was performed to localize Msp in T. denticola. Examination of negatively stained whole mounts identified substantial amounts of Msp in sonicated organisms. IEM of ultrathin-sectioned, intact treponemes also demonstrated that the preponderance of antigen was unassociated with the outer membrane. Lastly, immunofluorescence analysis of treponemes embedded in agarose gel microdroplets revealed that only minor portions of Msp are surface exposed. Taken as a whole, our findings challenge the widely held belief that Msp forms an array within the T. denticola outer membrane and demonstrate, instead, that it is predominantly periplasmic with only limited surface exposure. These findings also have implications for our evolving understanding of the contribution(s) of Msp/Tpr orthologs to treponemal physiology and disease pathogenesis.


Subject(s)
Bacterial Proteins , Porins/analysis , Treponema/chemistry , Animals , Antigens, Surface/analysis , Fluorescent Antibody Technique, Indirect , Microscopy, Immunoelectron , Peptidoglycan/analysis , Rats , Rats, Sprague-Dawley
3.
Radiat Environ Biophys ; 23(4): 235-43, 1984.
Article in English | MEDLINE | ID: mdl-6093184

ABSTRACT

Using ESR we have demonstrated the formation of the ascorbate free radical from sodium ascorbate, methylene blue and light. In oxygen uptake experiments we have observed the production of hydrogen peroxide while spin trapping experiments have revealed the iron catalyzed production of the hydroxyl free radical in this system. The presence of this highly reactive radical suggests that it could be the radical that initiates free radical damage in this photodynamic system.


Subject(s)
Ascorbic Acid , Hydrogen Peroxide , Hydroxides , Methylene Blue , Cyclic N-Oxides , Electron Spin Resonance Spectroscopy , Hydroxyl Radical , Ophthalmic Solutions/adverse effects , Oxygen , Photochemistry , Spin Labels
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