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Mechanism of Action at the Molecular Level of the Antiviral Drug 3(2H)-Isoflavene against Type 2 Poliovirus

Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome,¹ Istituto di Ricerche di Biologia Molecolare P. Angeletti, Pomezia, Italy²

Received 27 August 2003/ Returned for modification 4 November 2003/ Accepted 16 January 2004

The mechanism of action of the antiviral compound 3(2H)-isoflavene against Sabin type 2 poliovirus has been studied, and interference with virus uncoating was demonstrated. Isolation and sequencing of drug-resistant variants revealed single amino acid substitutions (I194M or D131V) in the VP1 capsid protein. While M194 is located in a hydrophobic pocket and should partially fill the space occupied by the isoflavene ring, V131 is exposed on the VP1 surface, forming a contact with VP4. The D131V mutation most likely induces local conformational changes in VP1 and/or VP4 that affect viral flexibility. Two dependent variants, N53S of VP1 and K58E of VP4, both located on the inner surface of the capsid, near the threefold axis of symmetry, were also selected. Both mutations affected viral stability, allowing the transition to 135S particles in the absence of drug, without the involvement of the viral receptor.