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 acts as a dual-function inhibitor of viral infection.Schematic overview of the anti-amyloid and antiviral effects of CLR01.DOI:http://dx.doi.org/10.7554/eLife.05397.029
© Copyright Policy
Related In: Results  -  Collection

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

fig10: CLR01 acts as a dual-function inhibitor of viral infection.Schematic overview of the anti-amyloid and antiviral effects of CLR01.DOI:http://dx.doi.org/10.7554/eLife.05397.029

Mentions: Despite the development of several different classes of topical microbicides, none have proven safe and effective at HIV prevention. The failure of topical microbicide candidates in previous clinical trials has been attributed to lack of adherence (Van Damme et al., 2008; Marrazzo et al., 2015), adverse effects (McGowan et al., 2011), and a greatly diminished antiviral efficacy in the presence of semen (Neurath et al., 2006; Zirafi et al., 2014). This bodily fluid is not only the main vector for HIV transmission but also contains cationic amyloid fibrils that markedly increase viral infectivity (Castellano and Shorter, 2012; Münch et al., 2014). Various biological polyanions such as heparin or other glycosaminoglycans can prevent these cationic fibrils from enhancing HIV infection (Roan et al., 2009). Unfortunately, however, such anionic polymers have been unsuccessful in past clinical microbicide trials due to their poor bioavailability and induction of inflammatory responses in the genital tract, which actually augment HIV transmission by recruiting HIV-susceptible target cells to the genital mucosa (Lüscher-Mattli, 2000; van de Wijgert and Shattock, 2007). We have suggested that future microbicide endeavors should focus on agents that simultaneously and safely target HIV and the host factors that are exploited by the virus to facilitate its transmission (Castellano and Shorter, 2012; Zirafi et al., 2014; Roan and Münch, 2015). Here, we report that CLR01, a lysine- and arginine-specific molecular tweezer (Fokkens et al., 2005), not only counteracts the infection-enhancing activity of seminal amyloids and semen, but also directly destroys HIV virions (Figure 10). CLR01 is a highly promising topical microbicide candidate because it possesses potent antiviral and anti-amyloid activity, displays minimal toxicity in vivo (Prabhudesai et al., 2012; Attar et al., 2014; Ferreira et al., 2014), and is efficacious in human seminal fluid.10.7554/eLife.05397.029Figure 10.CLR01 acts as a dual-function inhibitor of viral infection.


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 acts as a dual-function inhibitor of viral infection.Schematic overview of the anti-amyloid and antiviral effects of CLR01.DOI:http://dx.doi.org/10.7554/eLife.05397.029
© Copyright Policy
Related In: Results  -  Collection

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

fig10: CLR01 acts as a dual-function inhibitor of viral infection.Schematic overview of the anti-amyloid and antiviral effects of CLR01.DOI:http://dx.doi.org/10.7554/eLife.05397.029
Mentions: Despite the development of several different classes of topical microbicides, none have proven safe and effective at HIV prevention. The failure of topical microbicide candidates in previous clinical trials has been attributed to lack of adherence (Van Damme et al., 2008; Marrazzo et al., 2015), adverse effects (McGowan et al., 2011), and a greatly diminished antiviral efficacy in the presence of semen (Neurath et al., 2006; Zirafi et al., 2014). This bodily fluid is not only the main vector for HIV transmission but also contains cationic amyloid fibrils that markedly increase viral infectivity (Castellano and Shorter, 2012; Münch et al., 2014). Various biological polyanions such as heparin or other glycosaminoglycans can prevent these cationic fibrils from enhancing HIV infection (Roan et al., 2009). Unfortunately, however, such anionic polymers have been unsuccessful in past clinical microbicide trials due to their poor bioavailability and induction of inflammatory responses in the genital tract, which actually augment HIV transmission by recruiting HIV-susceptible target cells to the genital mucosa (Lüscher-Mattli, 2000; van de Wijgert and Shattock, 2007). We have suggested that future microbicide endeavors should focus on agents that simultaneously and safely target HIV and the host factors that are exploited by the virus to facilitate its transmission (Castellano and Shorter, 2012; Zirafi et al., 2014; Roan and Münch, 2015). Here, we report that CLR01, a lysine- and arginine-specific molecular tweezer (Fokkens et al., 2005), not only counteracts the infection-enhancing activity of seminal amyloids and semen, but also directly destroys HIV virions (Figure 10). CLR01 is a highly promising topical microbicide candidate because it possesses potent antiviral and anti-amyloid activity, displays minimal toxicity in vivo (Prabhudesai et al., 2012; Attar et al., 2014; Ferreira et al., 2014), and is efficacious in human seminal fluid.10.7554/eLife.05397.029Figure 10.CLR01 acts as a dual-function inhibitor of viral infection.

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