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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

CLR01 does not impede adsorption of SEVI, PAP85-120, or SEM1(45-107) fibrils to the EM grid.Preformed SEVI, PAP85-120 fibrils, or SEM1(45-107) fibrils (20 µM) were treated with a 10-fold excess of CLR01 or buffer for 10 min and processed for TEM. Note the presence of abundant fibrils under each condition indicating that CLR01 does not impede fibril adsorption to the EM grid.DOI:http://dx.doi.org/10.7554/eLife.05397.006
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fig2s2: CLR01 does not impede adsorption of SEVI, PAP85-120, or SEM1(45-107) fibrils to the EM grid.Preformed SEVI, PAP85-120 fibrils, or SEM1(45-107) fibrils (20 µM) were treated with a 10-fold excess of CLR01 or buffer for 10 min and processed for TEM. Note the presence of abundant fibrils under each condition indicating that CLR01 does not impede fibril adsorption to the EM grid.DOI:http://dx.doi.org/10.7554/eLife.05397.006

Mentions: We excluded the possibility that CLR01 might impede adsorption of SEVI, PAP85-120, or SEM(45-107) fibrils to the EM grid. When we mixed CLR01 (or buffer) with preformed SEVI, PAP85-120, or SEM1(45-107) fibrils for 10 min (a time at which no fibril remodeling occurs; Figure 3A–C) and then adsorbed them to the grid, we observed abundant fibrils in both the CLR01 and buffer control conditions (Figure 2—figure supplement 2). Thus, any reduction in the presence of fibrils observed by EM can be attributed to inhibition of fibril assembly.10.7554/eLife.05397.010Figure 3.CLR01 rapidly remodels SEVI and PAP85-120 fibrils.


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 does not impede adsorption of SEVI, PAP85-120, or SEM1(45-107) fibrils to the EM grid.Preformed SEVI, PAP85-120 fibrils, or SEM1(45-107) fibrils (20 µM) were treated with a 10-fold excess of CLR01 or buffer for 10 min and processed for TEM. Note the presence of abundant fibrils under each condition indicating that CLR01 does not impede fibril adsorption to the EM grid.DOI:http://dx.doi.org/10.7554/eLife.05397.006
© Copyright Policy
Related In: Results  -  Collection

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

fig2s2: CLR01 does not impede adsorption of SEVI, PAP85-120, or SEM1(45-107) fibrils to the EM grid.Preformed SEVI, PAP85-120 fibrils, or SEM1(45-107) fibrils (20 µM) were treated with a 10-fold excess of CLR01 or buffer for 10 min and processed for TEM. Note the presence of abundant fibrils under each condition indicating that CLR01 does not impede fibril adsorption to the EM grid.DOI:http://dx.doi.org/10.7554/eLife.05397.006
Mentions: We excluded the possibility that CLR01 might impede adsorption of SEVI, PAP85-120, or SEM(45-107) fibrils to the EM grid. When we mixed CLR01 (or buffer) with preformed SEVI, PAP85-120, or SEM1(45-107) fibrils for 10 min (a time at which no fibril remodeling occurs; Figure 3A–C) and then adsorbed them to the grid, we observed abundant fibrils in both the CLR01 and buffer control conditions (Figure 2—figure supplement 2). Thus, any reduction in the presence of fibrils observed by EM can be attributed to inhibition of fibril assembly.10.7554/eLife.05397.010Figure 3.CLR01 rapidly remodels SEVI and PAP85-120 fibrils.

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