Abstract: Provided are compositions and methods for protecting a compound comprising a haloalkylamide moiety from metabolic transformation by hydrolases. In one aspect, the disclosure is directed to increasing the bioavailability and tissue delivery of a anti-HCV compound comprising a haloalkylamide moiety by protecting the compound from inactivation by carboxylesterases. Specific approaches for limiting metabolic transformation include use of carboxylesterase inhibitors to inhibit metabolism of the compound, or use of orally administered compositions designed to deliver the compound to the small intestine or large intestine. Further provided are methods of treating or preventing HCV infection in a subject.