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

Coated BSA does not antagonize the antiviral activity of CLR01.Microtiter plates were coated over night with the indicated amounts of BSA. After a 20-min incubation at room temperature, serial dilutions of CLR01 were added and incubated with HIV-1 for another 10 min at room temperature. With these mixtures, TZM-bl cells were infected. Infection rates were determined 3 days post infection. (A) Values represent mean β-galactosidase activities derived from triplicate infections ±SD (RLU/s: relative light units per second). (B) Values represent normalized mean infection rates derived from triplicate infections ±SD.DOI:http://dx.doi.org/10.7554/eLife.05397.019
© Copyright Policy
Related In: Results  -  Collection

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

fig5s2: Coated BSA does not antagonize the antiviral activity of CLR01.Microtiter plates were coated over night with the indicated amounts of BSA. After a 20-min incubation at room temperature, serial dilutions of CLR01 were added and incubated with HIV-1 for another 10 min at room temperature. With these mixtures, TZM-bl cells were infected. Infection rates were determined 3 days post infection. (A) Values represent mean β-galactosidase activities derived from triplicate infections ±SD (RLU/s: relative light units per second). (B) Values represent normalized mean infection rates derived from triplicate infections ±SD.DOI:http://dx.doi.org/10.7554/eLife.05397.019


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)

Coated BSA does not antagonize the antiviral activity of CLR01.Microtiter plates were coated over night with the indicated amounts of BSA. After a 20-min incubation at room temperature, serial dilutions of CLR01 were added and incubated with HIV-1 for another 10 min at room temperature. With these mixtures, TZM-bl cells were infected. Infection rates were determined 3 days post infection. (A) Values represent mean β-galactosidase activities derived from triplicate infections ±SD (RLU/s: relative light units per second). (B) Values represent normalized mean infection rates derived from triplicate infections ±SD.DOI:http://dx.doi.org/10.7554/eLife.05397.019
© Copyright Policy
Related In: Results  -  Collection

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

fig5s2: Coated BSA does not antagonize the antiviral activity of CLR01.Microtiter plates were coated over night with the indicated amounts of BSA. After a 20-min incubation at room temperature, serial dilutions of CLR01 were added and incubated with HIV-1 for another 10 min at room temperature. With these mixtures, TZM-bl cells were infected. Infection rates were determined 3 days post infection. (A) Values represent mean β-galactosidase activities derived from triplicate infections ±SD (RLU/s: relative light units per second). (B) Values represent normalized mean infection rates derived from triplicate infections ±SD.DOI:http://dx.doi.org/10.7554/eLife.05397.019
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