title: Respiratory syncytial virus infection in macaques is not suppressed by intranasal sprays of pyrimidine biosynthesis inhibitors.
abstract: There is imperious need for efficient therapies against ubiquitous and life-threatening respiratory viruses, foremost among them being the human respiratory syncytial virus (hRSV). Several research groups who performed functional screens for broad-spectrum antivirals identified compounds targeting the de novo pyrimidine biosynthesis pathway. Despite their strong antiviral activity in vitro, whether such antimetabolites are effective in vivo remains highly controversial. Here, we evaluated two potent pyrimidine biosynthesis inhibitors developed in our laboratory, IPPA17-A04 and GAC50, in a model of mild hRSV-infection in cynomolgus macaques. In this model, hRSV replication is restricted to the epithelium of the upper respiratory tract, and is compatible with a topical treatment by intranasal sprays. The local administration of palivizumab, a neutralizing anti-hRSV antibody used in clinics, significantly reduced virus replication. In contrast, pyrimidine biosynthesis inhibitors did not show any inhibitory effect on hRSV growth when delivered topically as experimented in our model. Our results should help to better define the potential applications of this class of antimetabolites in the treatment of viral infections.
authors.affiliation: Cynbiose SA, Marcy-l'Etoile, France; Institut Pasteur, Unité de Génomique Virale et Vaccination, Paris, France; CNRS, UMR3569, Paris, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Grandin
authors.affiliation: Institut Pasteur, Unité de Génomique Virale et Vaccination, Paris, France; CNRS, UMR3569, Paris, France.
authors.forename: Marianne-Lucas
authors.initials: ML
authors.lastname: Hourani
authors.affiliation: Institut Pasteur, Unité de Chimie et Biocatalyse, Paris, France; CNRS, UMR3523, Paris, France.
authors.forename: Yves L
authors.initials: YL
authors.lastname: Janin
authors.affiliation: Institut Curie, Centre de Recherche, Paris, France; CNRS, UMR3666, Paris, France; INSERM, U1143, Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Dauzonne
authors.affiliation: Institut Pasteur, Unité de Chimie et Biocatalyse, Paris, France; CNRS, UMR3523, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Munier-Lehmann
authors.affiliation: Cynbiose SA, Marcy-l'Etoile, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Paturet
authors.affiliation: Cynbiose SA, Marcy-l'Etoile, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Taborik
authors.affiliation: Université de Caen-Basse-Normandie, EA 4655-U2RM, Laboratoire de Virologie, CHU de Caen, France.
authors.forename: Astrid
authors.initials: A
authors.lastname: Vabret
authors.affiliation: Cynbiose SA, Marcy-l'Etoile, France. Electronic address: hugues.contamin@cynbiose.com.
authors.forename: Hugues
authors.initials: H
authors.lastname: Contamin
authors.affiliation: Institut Pasteur, Unité de Génomique Virale et Vaccination, Paris, France; CNRS, UMR3569, Paris, France. Electronic address: frederic.tangy@pasteur.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Tangy
authors.affiliation: Institut Pasteur, Unité de Génomique Virale et Vaccination, Paris, France; CNRS, UMR3569, Paris, France. Electronic address: pierre-olivier.vidalain@parisdescartes.fr.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Vidalain
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D000090722:Dihydroorotate Dehydrogenase; D004195:Disease Models, Animal; D056945:Hep G2 Cells; D006801:Humans; D008251:Macaca; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors; D000069455:Palivizumab / Q000494:pharmacology; D011743:Pyrimidines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D018113:Respiratory Syncytial Virus, Human / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000963:Antimetabolites; D000998:Antiviral Agents; D000090722:Dihydroorotate Dehydrogenase; D011743:Pyrimidines; D000069455:Palivizumab; D044925:Oxidoreductases Acting on CH-CH Group Donors; C030986:pyrimidine
keywords: Antiviral compounds; Cynomolgus macaques; Dihydroorotate dehydrogenase; Pyrimidine biosynthesis inhibitors; Respiratory syncytial virus