title: Suramin interacts with the positively charged region surrounding the 5-fold axis of the EV-A71 capsid and inhibits multiple enterovirus A.
abstract: Suramin was previously shown to bind to the EV-A71 capsid through its naphthalenetrisulfonic acid groups, thereby reducing virus-cell binding and inhibiting viral replication. Here, we identify VP1-145 as the critical amino acid that accounts for the differential sensitivity of EVA-71 viruses to suramin. A single Q or G to E substitution at VP1-145 results in an approximately 30-fold shift of IC50or IC90values reproducing the inhibition profile observed with field isolates expressing either the 145Q or E mutation. Our data support the conclusion that suramin binds to the positively charged region surrounding the 5-fold axis of the capsid and consequently blocks the virus attachment and entry into host cells. In order to assess the antiviral-spectrum of suramin, we analyzed 18 representative enteroviruses: A (n = 7), B (n = 5), C (n = 5) and D (n = 1). We show that suramin potency is restricted to enterovirus A species. Clinical development of suramin is further supported by pharmacokinetic data demonstrating bioactive plasma levels after a single dose intramuscular administration in macaques. Altogether, our findings support the clinical development of suramin as a novel entry inhibitor for the treatment of enterovirus A infections.
authors.affiliation: Unit of Anti-infective Research, Institut Pasteur of Shanghai, Chinese Academy of Sciences, 320 Yueyang Road, 200031, Shanghai, China.|Laboratory of Viral Pathogenesis, Institut Pasteur, 28 Rue du Docteur Roux, 75724, Paris, France.
authors.forename: Peijun
authors.initials: P
authors.lastname: Ren
authors.affiliation: Unit of Anti-infective Research, Institut Pasteur of Shanghai, Chinese Academy of Sciences, 320 Yueyang Road, 200031, Shanghai, China.
authors.forename: Yimei
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: HONZ Pharma, 26FL, Dongshan Square, 69 Xian Lie Zhong Rd, 510095, Guangzhou, China.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Wang
authors.affiliation: HONZ Pharma, 26FL, Dongshan Square, 69 Xian Lie Zhong Rd, 510095, Guangzhou, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Hong
authors.affiliation: Unit of Biology of Enteric Viruses, Institut Pasteur, 25 Rue du Docteur Roux, 75724, Paris, France.|INSERM U994, Institut National de Santé et de La Recherche Médicale, Paris, France.
authors.forename: Françis
authors.initials: F
authors.lastname: Delpeyroux
authors.affiliation: Laboratory of Viral Pathogenesis, Institut Pasteur, 28 Rue du Docteur Roux, 75724, Paris, France.
authors.forename: Fernando
authors.initials: F
authors.lastname: Arenzana-Seisdedos
authors.affiliation: Unit of Anti-infective Research, Institut Pasteur of Shanghai, Chinese Academy of Sciences, 320 Yueyang Road, 200031, Shanghai, China.|Shandong University-Helmholtz Institute of Biotechnology, 168 Zhuzhou Road, 266101, Qingdao, Shandong, China.|Qingdao Municipal Center for Disease Control &Prevention, 175 Shandong Road, 266033, Qingdao, China.
authors.forename: Ralf
authors.initials: R
authors.lastname: Altmeyer
mesh_terms: D000818:Animals; D036022:Capsid Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004770:Enterovirus / Q000145:classification / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D006207:Half-Life; D006801:Humans; D008252:Macaca fascicularis; D016296:Mutagenesis; D010802:Phylogeny; D013498:Suramin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
chemical_list: D036022:Capsid Proteins; D013498:Suramin