Evidence that nonspecific inhibitors of viral entry would be a valuable complement to the antiviral arsenal and might also be considered as elements of combination therapy with more specific inhibitors. Despite the encouraging in vitro data on the efficacy of CQ as an antiviral, previous studies that have sought to demonstrate its in vivo efficacy have been less successful. Studies in mouse models of influenza and in hamster and ferret models of Nipah virus have failed to demonstrate that CQ affects the duration or severity of disease. Clinical studies of CQ monotherapy against Chikungunya and Dengue virus show that when CQ is dosed as for antimalarial use against an established human viral infection, it does not appear to impact disease severity or time to resolution. 1346527-98-7 Importantly, the THR1442 customer reviews design of these studies did not address the early stages of infection. For this reason, the protective effect of CQ in the murine EBOV challenge model is encouraging. None of the reported studies address the pharmacodynamics of the antiviral activity by demonstrating that the compound accumulates in the relevant tissue or compartments where the virus is replicating in vivo. Chloroquine has a large volume of distribution, which suggests that its rapid dissemination into extravascular tissues may impact its inhibitory activity. Clearly, the spectrum of viruses for which this class of compounds would be useful in vivo will be strongly determined by this factor, as well as by the potency of the compound itself in inhibiting specific steps in viral replication. Improvements in formulation, such as encapsulation within liposomes may also be of utility in modifying the pharmacokinetics of CQ in vivo. The antiviral activity of CQ may serve as an initial starting point for antiviral development through optimization of the 4AQ scaffold and by exploiting the decades of experience in toxicological investigation for this class of compounds. Significant effort has been expended in optimizing derivatives of CQ for malaria strains that have acquired resistance. By optimizing the antiviral activity of these compounds for short- or intermediate-term therapeutic dosing, it should be possible to develop analogs with entirely different properties than those required for antimalarial activity, inclu