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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

Poly-L-lysine counteracts the antiviral activity of CLR01.CLR01 (40 µM) was titrated with poly-L-lysine. After a 10 min incubation with HIV-1 these mixtures were 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 ±SEM. Unpaired t-tests were used to compare the buffer control to the CLR01 condition at each poly-L-lysine concentration (ns denotes not significant; * denotes p < 0.05; ** denotes p < 0.01).DOI:http://dx.doi.org/10.7554/eLife.05397.018
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fig5s1: Poly-L-lysine counteracts the antiviral activity of CLR01.CLR01 (40 µM) was titrated with poly-L-lysine. After a 10 min incubation with HIV-1 these mixtures were 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 ±SEM. Unpaired t-tests were used to compare the buffer control to the CLR01 condition at each poly-L-lysine concentration (ns denotes not significant; * denotes p < 0.05; ** denotes p < 0.01).DOI:http://dx.doi.org/10.7554/eLife.05397.018

Mentions: Exposure of CLR01 to poly-L-lysine prior to incubation with virions abrogated its anti-HIV-1 activity in a dose-dependent manner (Figure 5—figure supplement 1). Near-complete inhibition was achieved with 75 nM poly-L-lysine. Thus, the lysine-binding cavity of CLR01 plays an important role in the antiviral (Figure 5; Figure 5—figure supplement 1) and anti-amyloid (Figure 2; Figure 2—figure supplements 3, 5; Figure 3; Figure 3—figure supplement 1) activities of CLR01.


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)

Poly-L-lysine counteracts the antiviral activity of CLR01.CLR01 (40 µM) was titrated with poly-L-lysine. After a 10 min incubation with HIV-1 these mixtures were 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 ±SEM. Unpaired t-tests were used to compare the buffer control to the CLR01 condition at each poly-L-lysine concentration (ns denotes not significant; * denotes p < 0.05; ** denotes p < 0.01).DOI:http://dx.doi.org/10.7554/eLife.05397.018
© Copyright Policy
Related In: Results  -  Collection

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

fig5s1: Poly-L-lysine counteracts the antiviral activity of CLR01.CLR01 (40 µM) was titrated with poly-L-lysine. After a 10 min incubation with HIV-1 these mixtures were 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 ±SEM. Unpaired t-tests were used to compare the buffer control to the CLR01 condition at each poly-L-lysine concentration (ns denotes not significant; * denotes p < 0.05; ** denotes p < 0.01).DOI:http://dx.doi.org/10.7554/eLife.05397.018
Mentions: Exposure of CLR01 to poly-L-lysine prior to incubation with virions abrogated its anti-HIV-1 activity in a dose-dependent manner (Figure 5—figure supplement 1). Near-complete inhibition was achieved with 75 nM poly-L-lysine. Thus, the lysine-binding cavity of CLR01 plays an important role in the antiviral (Figure 5; Figure 5—figure supplement 1) and anti-amyloid (Figure 2; Figure 2—figure supplements 3, 5; Figure 3; Figure 3—figure supplement 1) activities of CLR01.

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