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The highly abundant GTP binding protein elongation factor Tu (EF-Tu) fulfills multiple roles in bacterial protein biosynthesis. Phage-displayed peptides with high affinity for EF-Tu were selected from a library of approximately 4.7 x 10(11) different peptides. The lack of sequence homology among the identified EF-Tu ligands demonstrates promiscuous peptide binding by EF-Tu. Homolog shotgun scanning of an EF-Tu ligand was used to dissect peptide molecular recognition by EF-Tu. All homolog shotgun scanning selectants bound to EF-Tu with higher affinity than the starting ligand. Thus, homolog shotgun scanning can simultaneously optimize binding affinity and rapidly provide detailed structure activity relationships for multiple side chains of a polypeptide ligand. The reported peptide ligands do not compete for binding to EF-Tu with various antibiotic EF-Tu inhibitors, and could identify an EF-Tu peptide binding site distinct from the antibiotic inhibitory sites.

Vatiquinone is a small‐molecule inhibitor of 15‐lipoxygenase in phase 3 development for patients with mitochondrial disease and Friedreich ataxia. The objective of this analysis was to determine the effect of vatiquinone on the pharmacokinetic profile of rosuvastatin, a breast cancer resistance protein substrate. In vitro investigations demonstrated potential inhibition of BCRP by vatiquinone (half maximal inhibitory concentration, 3.8 µM). An open‐label, fixed‐sequence drug‐drug interaction study in healthy volunteers was conducted to determine the clinical relevance of this finding. Subjects received a single dose of 20‐mg rosuvastatin followed by a 7‐day washout. On days 8 through 14, subjects received 400 mg of vatiquinone 3 times daily. On day 12, subjects concomitantly received a single dose of 20‐mg rosuvastatin. The geometric mean ratio for maximum plasma concentration was 77.8%; however, the rosuvastatin disposition phase appeared unaffected. The geometric mean ratios for the area under the plasma concentration–time curve from time 0 to time t and from time 0 to infinity were 103.2% and 99.9%, respectively. Mean rosuvastatin apparent elimination half‐life was similar between treatment groups. These results demonstrate that vatiquinone has no clinically relevant effect on the pharmacokinetics of rosuvastatin. [ABSTRACT FROM AUTHOR]

Vatiquinone, a 15‐lipoxygenase inhibitor, is in development for patients with Friedreich's ataxia. Physiologically based pharmacokinetic (PBPK) modeling addressed drug–drug interaction gaps without additional studies. A PBPK model (Simcyp Simulator version 21, full model) was developed using parameters obtained from in vitro studies, in silico estimation and optimization, and two clinical studies. A venous blood dosing model best characterized vatiquinone lymphatic absorption. Apparent oral clearance (CL/F) was used to optimize intrinsic clearance (CLint). Intestinal availability (Fg) was estimated using the hybrid flow term (Qgut), unbound fraction in the enterocytes (fugut), and gut intrinsic metabolic clearance (CLuG,int). Renal clearance (CLR) was set to zero. Assuming an Fa of 1, CYP3A4 contribution (fmCYP3A4) was further optimized. The PBPK model was verified with two clinical studies and demonstrated that it adequately characterized vatiquinone PK. As a perpetrator, the model predicted no risk for vatiquinone to significantly alter the drug exposures of CYP3A4 and CYP1A2 substrates as evident bynegligible reduction in both midazolam and caffeine area under the curve (AUC)inf and Cmax. As a victim, the model predicted that vatiquinone exposures are weakly influenced by moderate CYP3A4 inhibitors and inducers. With fluconazole coadministration, vatiquinone AUCinf and Cmax increased by nearly 50% and 25%, respectively. With efavirenz coadministration, vatiquinone AUCinf and Cmax decreased by approximately 20% and 10%, respectively. Results suggested that vatiquinone does not significantly impact CYP3A4 and CYP1A2 substrates and that moderate CYP3A4 inhibitors and inducers weakly impact vatiquinone AUC. [ABSTRACT FROM AUTHOR]