Locking out viral replication.

by a single A→U point mutation3. Both the benzimidazole derivative and the mutation reduce the production of viral proteins by approximately 80%, likely by preventing formation of the complete 80S eukaryotic ribosome. Hence this small molecule does not function by competitively inhibiting the interaction between the IRES and its target. Instead, it affects IRESdriven viral protein synthesis by altering RNA conformational properties at a step where mutual adaptation between the IRES and its ribosomal target is required for activation. In the decade-long search for small-molecule drugs that target RNA, the focus has often been on disrupting the interactions between RNA and proteins. As with protein–protein complexes, abrogating such interactions has proven very difficult. Proteins have large surface areas and depends on the recognition of the 5′ and 3′ ends of mature cellular mRNAs. Although the HCV IRES adopts conserved secondary and tertiary structures, like many other RNAs it retains conformational flexibility to recognize and adapt to various cellular targets (Fig. 1). By monitoring the distance between fluorescent tags on a viral RNA construct, Parsons et al. show that the benzimidazole derivative discovered at Ibis captures a specific structure within the HCV IRES domain, locking it into a conformation that is unable to interact productively with the host translation machinery (Fig. 1). Subdomain IIa of the HCV IRES adopts an L shape and induces significant conformational changes in the 40S ribosomal subunit when it binds5–7. The benzimidazole derivative analyzed by Parsons et al. binds to the ‘elbow’ of subdomain IIa, and in doing so it fixes the interhelical Over 3% of the world population is infected with the hepatitis C virus (HCV)1. There is no vaccine for this, and the best treatment available (interferon-ribavirin combination) is effective in fewer than half of patients. Several drug candidates are currently in clinical trials that inhibit the virally encoded HCV protease, a classical target for intervention. However, this member of the Flaviviridae virus family is prone to frequent mutation, making the development of prophylactic and curative treatment options with sustained efficacy particularly challenging. Interestingly, some of the most highly conserved regions of the HCV genome are found in untranslated regions. The HCV virus encodes an internal ribosomal entry site (IRES) at the 5′ end of its genomic RNA that is responsible for initiation of protein synthesis. A small molecule recently discovered at Ibis Therapeutics binds a critical structure within the HCV IRES and inhibits its function2, and a study in this issue reveals its mechanism of inhibition. The benzimidazole derivative locks the RNA conformation and prevents the IRES from assuming its functional structure during initiation of protein synthesis. Viral replication studies by Parsons et al. suggest that this molecule may represent a new class of antivirals that function by directly binding to viral RNA3. IRESs are highly structured RNA elements present in the genome of many retroviruses (and a few cellular genes) that control the initiation of protein synthesis. The HCV IRES directly interacts with the host 40S ribosomal subunit and helps recruit eukaryotic translational initiation factors4. This mechanism bypasses the canonical protein synthesis pathway, which Locking out viral replication