Inhibition of Measles Virus Replication by 5′-Nor Carbocyclic Adenosine Analogues

Abstract

Despite intense efforts to increase vaccine coverage, measles virus (MV) still causes significant morbidity and mortality in the world, sometimes as the result of severe, chronic, lethal disease. In an effort to develop therapies to supplement immunization strategies, a number of 5′-nor carbocyclic adenosine analogues were evaluated for anti-MV activity in CV-1 monkey kidney cells. Of those compounds tested, those either unsubstituted at C4 or possessing a hydroxyl, azido or amino substituent at that position were the most active, with particularly significant inhibition of MV, strain Chicago-1. The EC50 values against this strain ranged from <0.1 to 1 mg/ml, as determined by cytopathic effect reduction assay, and confirmed by neutral red uptake. By virus yield reduction assay (+)-(1 S,2S,3R,4S)-4-(6′-amino-9'H-purin-9′- yl)cyclopentane-1,2,3-triol (2) (-)-(1R,2S,3R)-1-(6′- amino-9'H-purin-9′-yl)-2,3-dihydoxycyclopent-4- ene (3) (-)-(1R,2S,3R)-1-(6-amino-9H-purin-9- yl)cyclopentane-2,3-dihydoxycyclopentane (5) and (-)-(1R,2R,3R,4S)-4-amino-1-(6-amino-9H-purin-9- yl)cyclopentane-2,3-diol (8) were the most potent compounds tested, all with EC90 values of <0.4 mg/ml. Compounds 3 and 5 were also tested against other MV strains, and similarly inhibited those strains except for four designated as Bil, Edmonston, SA and X-1108. Compound 8 did not potently inhibit these other MV strains. In addition, 3, 5 and 8 demonstrated synergistic (additive) inhibition of MV replication in combination with ribavirin at several concentrations. Compounds 3, 5 and 8 were also potent MV inhibitors even when added to infected cells 24 h after virus exposure. None of these three compounds was virucidal at concentrations that inhibited viral replication as determined by virus yield reduction assay. Most compounds tested were also not toxic at concentrations >100 mg/ml in actively growing and stationary-phase cells. Results suggest that these compounds may be clinically useful anti-MV virus agents.