The AGMA1 poly(amidoamine) inhibits the infectivity of herpes simplex virus in cell lines, in human cervicovaginal histocultures, and in vaginally infected mice

Abstract

a b s t r a c tThe development of topical microbicides is a valid approach to protect the genital mucosa from sexually transmitted infections that cannot be contained with effective vaccination, like HSV and HIV infections. A suitable target of microbicides is the interaction between viral proteins and cell surface heparan sulfate proteoglycans (HSPGs). AGMA1 is a prevailingly cationic agmatine-containing polyamidoamine polymer previously shown to inhibit HSPGs dependent viruses, including HSV-1, HSV-2, and HPV-16. The aim of this study was to elucidate the mechanism of action of AGMA1 against HSV infection and assess its antiviral efficacy and biocompatibility in preclinical models. The results show AGMA1 to be a non-toxic inhibitor of HSV infectivity in cell cultures and human cervicovaginal histocultures. Moreover, it significantly reduced the burden of infection of HSV-2 genital infection in mice. The investigation of the mechanism of action revealed that AGMA1 reduces cells susceptibility to virus infection by binding to cell surface HSPGs thereby preventing HSV attachment. This study indicates that AGMA1 is a promising candidate for the development of a topical microbicide to prevent sexually transmitted HSV infections.

Polyamidoamines: Versatile Bioactive Polymers with Potential for Biotechnological Applications

“…The AGMA1 activity against HSV-1 and HSV-2 infection was also ascertained on reconstructed human epithelia, namely ectocervico-vaginal tissue (EpiVaginal™), without eliciting inflammation. The same inhibitory effect and lack of inflammatory activity was subsequently confirmed in vivo after topical administration to female mice [141]. Moreover, AGMA1 did not influence the vaginal pH, since proved inactive towards Lactobacillus spp.…”

“…To confirm this, it was demonstrated that AGMA1 interacts with either immobilized heparin or cellular heparan sulfates, in the latter case preventing HPV attachment to the cell surface [140]. Accordingly, AGMA1 did not kill the virus, but blocked the infection transmission from cell to cell [141].…”

Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism

“…The binding between viruses and HSPGs usually occurs via the interaction of closely-packed arrangements of multiple basic amino acids on the proteins, that constitute the VAL, with the negatively charged sulfated groups of heparan sulfate (HS) in the glycocalix of the cell surface. 9 A long list of HSPG mimicking materials such as heparin, 10,11 sulfated polysaccharides, 9,12 or sulfonic acid decorated polymers, dendrimers, and nanoparticles [13][14][15][16][17] have been tested and shown to exert potent virustatic activity in vitro, none have shown efficacy in humans. The only three polyanionic anti-HIV-1 microbicides that reached phase III clinical trial (i.e.…”

Heparan Sulfate Proteoglycans: A Multifaceted Target for Novel Approaches in Antiviral Drug Discovery

“…The agmantine-containing poly(amidoamine)s polymer AGMA1 is another interesting microbicide candidate that exerts a multitarget antiviral activity. It binds to HSPG thus preventing the infection of several HSPG-dependent viruses including HSV, HPV and RSV [29][30][31]. Of note, AGMA1 inhibited HSV-2 infection in human cervicovaginal histocultures and significantly reduced the burden of HSV-2 infection in vaginally infected mice [29] …”