Limits...
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

CLR01 is not cytotoxic.TZM-bl cells were incubated for 3 days with the indicated concentrations of (A) CLR01 and CLR03 and (B) CLR01, nonoxynol 9 (N9), sodium dodecyl sulfate (SDS) and Triton X-100 (TX-100). Cell viability was measured in an MTT assay. Values represent means ±SD (n = 3).DOI:http://dx.doi.org/10.7554/eLife.05397.016
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4536748&req=5

fig4s3: CLR01 is not cytotoxic.TZM-bl cells were incubated for 3 days with the indicated concentrations of (A) CLR01 and CLR03 and (B) CLR01, nonoxynol 9 (N9), sodium dodecyl sulfate (SDS) and Triton X-100 (TX-100). Cell viability was measured in an MTT assay. Values represent means ±SD (n = 3).DOI:http://dx.doi.org/10.7554/eLife.05397.016

Mentions: The combined effects of CLR01 on fibril architecture (Figures 2, 3) and the formation of fibril–virion complexes (Figure 4A–C) led us to investigate whether the tweezer might diminish the infection-enhancing property of seminal amyloids. First, we analyzed possible cytotoxic effects of the tweezer in TZM-bl cells, a HIV reporter cell line commonly used to study virus infection (Münch et al., 2007; Usmani et al., 2014). We found that CLR01 and CLR03 did not cause cytotoxic effects at concentrations up to 500 µM, whereas the surfactants Triton X-100, nonoxynol 9 and sodium dodecyl sulfate (SDS) were highly toxic (Figure 4—figure supplement 3). Thus, CLR01 does not act in a manner similar to non-ionic or anionic surfactants.


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)

CLR01 is not cytotoxic.TZM-bl cells were incubated for 3 days with the indicated concentrations of (A) CLR01 and CLR03 and (B) CLR01, nonoxynol 9 (N9), sodium dodecyl sulfate (SDS) and Triton X-100 (TX-100). Cell viability was measured in an MTT assay. Values represent means ±SD (n = 3).DOI:http://dx.doi.org/10.7554/eLife.05397.016
© Copyright Policy
Related In: Results  -  Collection

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

fig4s3: CLR01 is not cytotoxic.TZM-bl cells were incubated for 3 days with the indicated concentrations of (A) CLR01 and CLR03 and (B) CLR01, nonoxynol 9 (N9), sodium dodecyl sulfate (SDS) and Triton X-100 (TX-100). Cell viability was measured in an MTT assay. Values represent means ±SD (n = 3).DOI:http://dx.doi.org/10.7554/eLife.05397.016
Mentions: The combined effects of CLR01 on fibril architecture (Figures 2, 3) and the formation of fibril–virion complexes (Figure 4A–C) led us to investigate whether the tweezer might diminish the infection-enhancing property of seminal amyloids. First, we analyzed possible cytotoxic effects of the tweezer in TZM-bl cells, a HIV reporter cell line commonly used to study virus infection (Münch et al., 2007; Usmani et al., 2014). We found that CLR01 and CLR03 did not cause cytotoxic effects at concentrations up to 500 µM, whereas the surfactants Triton X-100, nonoxynol 9 and sodium dodecyl sulfate (SDS) were highly toxic (Figure 4—figure supplement 3). Thus, CLR01 does not act in a manner similar to non-ionic or anionic surfactants.

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