1. USC-087 protects Syrian hamsters against lethal challenge with human species C adenoviruses
- Author
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Mark N. Prichard, Karoly Toth, Jacqueline F. Spencer, Ann E. Tollefson, Boris A. Kashemirov, Elke Lipka, Dawn Reyna, Caroll B. Hartline, Baoling Ying, Jinglei Lyu, Charles E. McKenna, Cheryl Harteg, William S. M. Wold, Eric T. Richard, and Jiajun Fan
- Subjects
0301 basic medicine ,endocrine system ,medicine.medical_treatment ,animal diseases ,viruses ,030106 microbiology ,Organophosphonates ,Hamster ,Administration, Oral ,Hematopoietic stem cell transplantation ,Median lethal dose ,Antiviral Agents ,Article ,Adenovirus Infections, Human ,03 medical and health sciences ,chemistry.chemical_compound ,Immunocompromised Host ,Virology ,medicine ,Animals ,Disseminated disease ,Prodrugs ,Pharmacology ,biology ,Mesocricetus ,business.industry ,Adenine ,Adenoviruses, Human ,virus diseases ,biology.organism_classification ,medicine.disease ,Survival Analysis ,Disease Models, Animal ,030104 developmental biology ,Treatment Outcome ,Viral replication ,Adenine analog ,chemistry ,Liver ,Tyrosine ,business ,Cidofovir - Abstract
Human adenoviruses (AdV) cause generally mild infections of the respiratory and GI tracts as well as some other tissues. However, AdV can cause serious infection in severely immunosuppressed individuals, especially pediatric patients undergoing allogeneic hematopoietic stem cell transplantation, where mortality rates are up to 80% with disseminated disease. Despite the seriousness of AdV disease, there are no drugs approved specifically to treat AdV infections. We report here that USC-087, an N-alkyl tyrosinamide phosphonate ester prodrug of HPMPA, the adenine analog of cidofovir, is highly effective against multiple AdV types in cell culture. USC-087 is also effective against AdV-C6 in our immunosuppressed permissive Syrian hamster model. In this model, hamsters are immunosuppressed by treatment with high dose cyclophosphamide. Injection of AdV-C6 (or AdV-C5) intravenously leads to a disseminated infection that resembles the disease seen in humans, including death. We have tested the efficacy of orally-administered USC-087 against the median lethal dose of intravenously administered AdV-C6. USC-087 completely prevented or significantly decreased mortality when administered up to 4 days post challenge. USC-087 also prevented or significantly decreased liver damage caused by AdV-C6 infection, and suppressed virus replication even when administered 4 days post challenge. These results imply that USC-087 is a promising candidate for drug development against HAdV infections.
- Published
- 2017