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While a vaccine against chikungunya virus was recently approved, no vaccines currently exist for other alphaviruses, nor are there antiviral drugs for the treatment of alphavirus infections. Alphaviruses have positive\u2010strand RNA genomes, and their RNA replication is coordinated by activities of the multifunctional nonstructural protein 2 (nsP2), a helicase\u2010protease and a subunit of viral RNA replicase. We provide a comprehensive overview of nsP2 functions and inhibitors of its activities for their potential as effective antivirals. 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