Susceptibility to metabolism is a common issue with the tert-butyl group on compounds of medicinal interest. We demonstrate an approach of removing all the fully sp 3 C−Hs from a tert-butyl group: replacing some C−Hs with C−Fs and increasing the s-character of the remaining C−Hs. This approach gave a trifluoromethylcyclopropyl group, which increased metabolic stability. Trifluoromethylcyclopropyl-containing analogues had consistently higher metabolic stability in vitro and in vivo compared to their tert-butyl-containing counterparts.

The search for novel therapeutic interventions for viral disease is a challenging pursuit, hallmarked by the paucity of antiviral agents currently prescribed. Targeting of viral proteins has the inextricable challenge of rise of resistance. Safe and effective vaccines are not possible for many viral pathogens. New approaches are required to address the unmet medical need in this area. We undertook a cell-based high-throughput screen to identify leads for development of drugs to treat respiratory syncytial virus (RSV), a serious pediatric pathogen. We identified compounds that are potent (nanomolar) inhibitors of RSV in vitro in HEp-2 cells and in primary human bronchial epithelial cells and were shown to act postentry. Interestingly, two scaffolds exhibited broad-spectrum activity among multiple RNA viruses. Using the chemical matter as a probe, we identified the targets and identified a common cellular pathway: the de novo pyrimidine biosynthesis pathway. Both targets were validated in vitro and showed no significant cell cytotoxicity except for activity against proliferative B- and T-type lymphoid cells. Corollary to this finding was to understand the consequences of inhibition of the target to the host. An in vivo assessment for antiviral efficacy failed to demonstrate reduced viral load, but revealed microscopic changes and a trend toward reduced pyrimidine pools and findings in histopathology. We present here a discovery program that includes screen, target identification, validation, and druggability that can be broadly applied to identify and interrogate other host factors for antiviral effect starting from chemical matter of unknown target/mechanism of action.

Advances in the design of permeable peptides and in the synthesis of large arrays of macrocyclic peptides with diverse amino acids have evolved on parallel but independent tracks. Less precedent combines their respective attributes, thereby limiting the potential to identify permeable peptide ligands for key targets. Herein, we present novel 6-, 7-, and 8-mer cyclic peptides (MW 774−1076 g•mol −1 ) with passive permeability and oral exposure that feature the amino acids and thioether ring-closing common to large array formats, including DNA-and RNA-templated synthesis. Each oral peptide herein, selected from virtual libraries of partially N-methylated peptides using in silico methods, reflects the subset consistent with low energy conformations, low desolvation penalties, and passive permeability. We envision that, by retaining the backbone N-methylation pattern and consequent bias toward permeability, one can generate large peptide arrays with sufficient side chain diversity to identify permeability-biased ligands to a variety of protein targets.

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