Nucleoside analogs were investigated for their potential to inhibit cowpox virus (a surrogate for
variola and monkeypox viruses) in cell culture and in lethal
respiratory infections in mice. Cell culture
antiviral activity was determined by plaque reduction assays, with cytotoxicity determined by cell proliferation assays. Selectivity indices (SI's, 50% cytotoxic concentration divided by 50% virus-inhibitory concentration) were determined for 15 compounds. Three arabinofuranosyl (Ara)
nucleosides showed activity in mouse mammary
tumor (C127I) cells:
guanine (
Ara-G),
thymine (
Ara-T), and
adenine (
Ara-A) with SI's of 113, 61, and 95, respectively. The 2'-fluoro-Ara
nucleosides of 5-F-cytosine (
FIAC),
5-methyluracil (
FMAU), and
5-iodouracil (
FIAU) exhibited SI's of 148, 77, and 29, respectively. Other potent compounds included
cidofovir (a positive control) and
3'-O-methyladenosine, with SI values of 164 and 56, respectively. In general, assays performed in African green monkey kidney (Vero) cells produced lower SI's than in C127I cells, except for
5-iodo-2'-deoxyuridine (IDU) which had an SI of > 71 in Vero cells and 3.1 in C127I cells. Intranasal
infection of mice with cowpox virus was followed a day later by twice daily intraperitoneal treatment with compounds for 5 days.
Ara-A was active at 300 mg/kg/day (40% survival),
FMAU at 100 mg/kg/day (70% survival), and
cidofovir (given for 1 day only) at 100 mg/kg (80-100% survival). None of the other compounds, including IDU, prevented death nor delayed the time to death.
Cidofovir had the best potential for treating
orthopoxvirus infections of those tested.