title: The AGMA1 poly(amidoamine) inhibits the infectivity of herpes simplex virus in cell lines, in human cervicovaginal histocultures, and in vaginally infected mice.
abstract: The 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.
authors: Dipartimento di Scienze Cliniche e Biologiche, Università degli Studi di Torino, 10043 Orbassano, Torino, Italy.
authors: Manuela
authors: M
authors: Donalisio
authors: Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, Università di Pisa, 56126 Pisa, Italy; ARPA Foundation, 56126 Pisa, Italy.
authors: Paola
authors: P
authors: Quaranta
authors: Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, Università di Pisa, 56126 Pisa, Italy.
authors: Flavia
authors: F
authors: Chiuppesi
authors: Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, Università di Pisa, 56126 Pisa, Italy.
authors: Mauro
authors: M
authors: Pistello
authors: Dipartimento di Scienze Cliniche e Biologiche, Università degli Studi di Torino, 10043 Orbassano, Torino, Italy.
authors: Valeria
authors: V
authors: Cagno
authors: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, 10125 Torino, Italy.
authors: Roberta
authors: R
authors: Cavalli
authors: Dipartimento di Oncologia, Università di Torino, 10043 Orbassano, Torino Italy.
authors: Marco
authors: M
authors: Volante
authors: Dipartimento di Medicina Molecolare e Traslazionale, Università di Brescia, 25123 Brescia, Italy.
authors: Antonella
authors: A
authors: Bugatti
authors: Dipartimento di Medicina Molecolare e Traslazionale, Università di Brescia, 25123 Brescia, Italy.
authors: Marco
authors: M
authors: Rusnati
authors: Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, 20133 Milano, Italy.
authors: Elisabetta
authors: E
authors: Ranucci
authors: Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, 20133 Milano, Italy.
authors: Paolo
authors: P
authors: Ferruti
authors: Dipartimento di Scienze Cliniche e Biologiche, Università degli Studi di Torino, 10043 Orbassano, Torino, Italy. Electronic address: david.lembo@unito.it.
authors: David
authors: D
authors: Lembo
mesh_terms: D000376:Agmatine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002584:Cervix Uteri / Q000166:cytology / Q000821:virology*; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D005260:Female; D006561:Herpes Simplex / Q000188:drug therapy; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D018258:Herpesvirus 2, Human / Q000187:drug effects*; D052162:Human papillomavirus 16 / Q000187:drug effects; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011073:Polyamines / Q000737:chemistry / Q000494:pharmacology*; D014709:Vero Cells
chemical_list: C521880:AGMA1 polymer; D000891:Anti-Infective Agents, Local; D000998:Antiviral Agents; D011073:Polyamines; D000376:Agmatine
keywords: Antiviral activity; Attachment inhibitor; Herpes simplex virus; Microbicide; Poly(amidoamine); Sexually transmitted infections