Cholic Acid-based Delivery System for Vaccine Candidates against Group A Streptococcus
Peptide-based vaccines are based on microbial proteins and use the body’s immune system to stimulate adaptive immunity against the microbe. An advantage of this approach is that peptides can be chemically synthesized, rather than biologically expressed; thus, they are fully defined and are free of biological contaminants. Peptide-based vaccines often need an adjuvant—an immunostimulant—and a delivery system to be efficacious. Liposomes can both boost protective immunity and serve as a route of delivery. In this Issue’s Featured Letter, Azuar et al. (DOI: 10.1021/acsmedchemlett.9b00239) report conjugating a peptide-based vaccine to cholic acid, which anchors the assembly into liposomes. The liposomes form into rods of a suitable size to be recognized by immune cells. The liposomes, as well as the peptide–cholic acid conjugate alone, were able to induce antibody titers against Group A Streptococcus clinical isolates. Future directions may include looking at cholic acid as an adjuvant for other peptide-based vaccines.
Structural and Molecular Insight into Resistance Mechanisms of First Generation cMET Inhibitors
The cMET receptor tyrosine kinase is an important target in non-small cell lung cancer, and several small-molecule inhibitors of cMET have been tested in the clinic. Recently, mutations in cMET that confer resistance have been reported in patients that have been treated with cMET inhibitors, but structural details of these mutations are relatively poorly understood. In this Issue, Collie et al. (DOI: 10.1021/acsmedchemlett.9b00276) report several X-ray crystal structures of cMET inhibitors bound to the D1228V mutant. These data are accompanied by a number of biophysical, biochemical, and cellular experiments. The structures reveal that the D1228V mutation does not directly interact with Type II inhibitors. Rather, the D1228V mutation causes an ordering of the so-called A-loop into an alpha-helical conformation. These studies could guide the design of other probe compounds for studying this and other cMET mutations.
Systematically Mitigating the p38α Activity of Triazole-based BET Inhibitors
Small-molecule inhibitors of Bromodomain and Extra Terminal (BET) proteins are being studied in a number of disease states, including cancer and inflammation. BET proteins include BRD2, BRD3, BRD4, and BRDT. The authors of this Letter previously reported an inhibitor that, among BET proteins, had good selectivity for BRD4-D1; however, it also had high binding affinity for p38α. In this Issue, Carlson et al. (DOI: 10.1021/acsmedchemlett.9b00227) carried out studies to alter the structure of the previously reported compound to enhance inhibition of BRD4-D1 and to reduce inhibition at p38α. The structure–activity relationship studies included examining a key hydrogen-bonding motif that had a large effect on binding to p38α. After several rounds of optimization, which was guided by an X-ray crystal structure of an analog bound to BRD4-D1, the authors developed a compound that was 15-fold more potent at BRD4-D1, but 100,000-fold less potent at p38α. Future studies may use this optimization approach at other BET targets.
