The innate immune response against invading microorganisms results in the deployment of phagocytes, including macrophages and dendritic cells to recognize pathogen-associated molecular patterns. Activation of Toll-like receptors (TLRs) expressed on these cells is a critical step in the initiation of this response, triggering the production of pro- and antiinflammatory cytokines to dampen microbial pathogenesis. Importantly, TLR activation also mediates dendritic cell maturation, a critical step in bridging the innate and adaptive arms of the immune system. Balancing the role of TLRs as central mediators of overlapping signaling pathways, whether directly through ligand interactions or via secondary adaptor molecules, mandates exquisite specificity. Further, understanding the immunopharmacology of TLR cross-talk during infection may help to provide insight into innate immunity and the mechanisms of immune-response subversion by pathogens. The continual and rapid emergence of drug resistance to traditional antimicrobial agents highlights the medical need for new treatment approaches. Herein, the discovery and development of TLR agonist and antagonist therapies for infectious diseases as adjunct to, or in place of, conventional treatment paradigms is discussed.

Chronic infection with hepatitis C virus (HCV) remains a global health concern. Using both in vitro and cell-based assays, a series of small molecule agents specific for the viral RNA-dependent RNA polymerase have been shown to interfere with viral RNA replication. Although no agents targeting this viral enzyme have demonstrated sustained efficacy in infected patients as measured by reduction in viral load at 72 weeks post-treatment, proof-of-concept has been achieved in the clinic. A comprehensive account of the structure-activity relationship for nucleoside and non-nucleoside inhibitors of HCV polymerase, as well as consideration of early discovery biologic approaches targeting NS5B are reviewed.

Human respiratory syncytial virus (HRSV) is a major respiratory viral pathogen causing moderate to severe upper and lower respiratory tract infections in all ages and across a wide range of patient populations. There are no currently approved vaccines and although a number of candidates are in various stages of development, the challenges are quite substantial. Presently, only a single agent is approved for HRSV prophylaxis, and therapeutic treatment options are severely limited and ineffective, particularly in the infant population. Antibody prophylaxis is restricted to use in populations at high-risk for hospitalization (infants under 35 weeks gestational age, infants with chronic lung disease, and infants with congenital heart disease). Aerosol administration of the guanosine analog ribavirin has been approved for the treatment of severe HRSV LRTI in both children and mechanically ventilated patients; however, there is still debate over its overall benefit and the risks associated with its use. Current therapy for those hospitalized due to HRSV is supportive. As such, there is great medical need for the development of agents to prevent and treat HRSV infections in all populations. Interestingly, many of the discovered agents against HRSV, both neutralizing antibodies and small molecules inhibitors, target the viral fusion (F) glycoprotein. In particular, three distinct chemical classes as exemplified by JNJ-2408068, VP-14637, and BMS-433771, which appear to block conformational intermediates of the viral fusion protein are reviewed.