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A molecular tweezer antagonizes seminal amyloids and HIV infection.

Lump E, Castellano LM, Meier C, Seeliger J, Erwin N, Sperlich B, Stürzel CM, Usmani S, Hammond RM, von Einem J, Gerold G, Kreppel F, Bravo-Rodriguez K, Pietschmann T, Holmes VM, Palesch D, Zirafi O, Weissman D, Sowislok A, Wettig B, Heid C, Kirchhoff F, Weil T, Klärner FG, Schrader T, Bitan G, Sanchez-Garcia E, Winter R, Shorter J, Münch J - Elife (2015)

Bottom Line: In this study, we establish that CLR01, a 'molecular tweezer' specific for lysine and arginine residues, inhibits the formation of infectivity-enhancing seminal amyloids and remodels preformed fibrils.We establish that CLR01 acts by binding to the target lysine and arginine residues rather than by a non-specific, colloidal mechanism.CLR01 counteracts both host factors that may be important for HIV transmission and the pathogen itself.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.

ABSTRACT
Semen is the main vector for HIV transmission and contains amyloid fibrils that enhance viral infection. Available microbicides that target viral components have proven largely ineffective in preventing sexual virus transmission. In this study, we establish that CLR01, a 'molecular tweezer' specific for lysine and arginine residues, inhibits the formation of infectivity-enhancing seminal amyloids and remodels preformed fibrils. Moreover, CLR01 abrogates semen-mediated enhancement of viral infection by preventing the formation of virion-amyloid complexes and by directly disrupting the membrane integrity of HIV and other enveloped viruses. We establish that CLR01 acts by binding to the target lysine and arginine residues rather than by a non-specific, colloidal mechanism. CLR01 counteracts both host factors that may be important for HIV transmission and the pathogen itself. These combined anti-amyloid and antiviral activities make CLR01 a promising topical microbicide for blocking infection by HIV and other sexually transmitted viruses.

No MeSH data available.


Related in: MedlinePlus

BSA does not antagonize the antiviral activity of CLR01.CLR01 (220 µM) was titrated with the indicated concentrations of BSA. HIV-1 was incubated with these mixtures for 10 min and then used to infect TZM-bl cells. Infection rates were determined 3 days post infection via a β-galactosidase assay. Values represent normalized mean infection rates derived from triplicate measurements ±SD. Unpaired t-tests were used to compare the buffer control to the CLR01 condition at each BSA concentration (** denotes p < 0.01; *** denotes p < 0.001).DOI:http://dx.doi.org/10.7554/eLife.05397.020
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fig5s3: BSA does not antagonize the antiviral activity of CLR01.CLR01 (220 µM) was titrated with the indicated concentrations of BSA. HIV-1 was incubated with these mixtures for 10 min and then used to infect TZM-bl cells. Infection rates were determined 3 days post infection via a β-galactosidase assay. Values represent normalized mean infection rates derived from triplicate measurements ±SD. Unpaired t-tests were used to compare the buffer control to the CLR01 condition at each BSA concentration (** denotes p < 0.01; *** denotes p < 0.001).DOI:http://dx.doi.org/10.7554/eLife.05397.020


A molecular tweezer antagonizes seminal amyloids and HIV infection.

Lump E, Castellano LM, Meier C, Seeliger J, Erwin N, Sperlich B, Stürzel CM, Usmani S, Hammond RM, von Einem J, Gerold G, Kreppel F, Bravo-Rodriguez K, Pietschmann T, Holmes VM, Palesch D, Zirafi O, Weissman D, Sowislok A, Wettig B, Heid C, Kirchhoff F, Weil T, Klärner FG, Schrader T, Bitan G, Sanchez-Garcia E, Winter R, Shorter J, Münch J - Elife (2015)

BSA does not antagonize the antiviral activity of CLR01.CLR01 (220 µM) was titrated with the indicated concentrations of BSA. HIV-1 was incubated with these mixtures for 10 min and then used to infect TZM-bl cells. Infection rates were determined 3 days post infection via a β-galactosidase assay. Values represent normalized mean infection rates derived from triplicate measurements ±SD. Unpaired t-tests were used to compare the buffer control to the CLR01 condition at each BSA concentration (** denotes p < 0.01; *** denotes p < 0.001).DOI:http://dx.doi.org/10.7554/eLife.05397.020
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4536748&req=5

fig5s3: BSA does not antagonize the antiviral activity of CLR01.CLR01 (220 µM) was titrated with the indicated concentrations of BSA. HIV-1 was incubated with these mixtures for 10 min and then used to infect TZM-bl cells. Infection rates were determined 3 days post infection via a β-galactosidase assay. Values represent normalized mean infection rates derived from triplicate measurements ±SD. Unpaired t-tests were used to compare the buffer control to the CLR01 condition at each BSA concentration (** denotes p < 0.01; *** denotes p < 0.001).DOI:http://dx.doi.org/10.7554/eLife.05397.020
Bottom Line: In this study, we establish that CLR01, a 'molecular tweezer' specific for lysine and arginine residues, inhibits the formation of infectivity-enhancing seminal amyloids and remodels preformed fibrils.We establish that CLR01 acts by binding to the target lysine and arginine residues rather than by a non-specific, colloidal mechanism.CLR01 counteracts both host factors that may be important for HIV transmission and the pathogen itself.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.

ABSTRACT
Semen is the main vector for HIV transmission and contains amyloid fibrils that enhance viral infection. Available microbicides that target viral components have proven largely ineffective in preventing sexual virus transmission. In this study, we establish that CLR01, a 'molecular tweezer' specific for lysine and arginine residues, inhibits the formation of infectivity-enhancing seminal amyloids and remodels preformed fibrils. Moreover, CLR01 abrogates semen-mediated enhancement of viral infection by preventing the formation of virion-amyloid complexes and by directly disrupting the membrane integrity of HIV and other enveloped viruses. We establish that CLR01 acts by binding to the target lysine and arginine residues rather than by a non-specific, colloidal mechanism. CLR01 counteracts both host factors that may be important for HIV transmission and the pathogen itself. These combined anti-amyloid and antiviral activities make CLR01 a promising topical microbicide for blocking infection by HIV and other sexually transmitted viruses.

No MeSH data available.


Related in: MedlinePlus