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211ChemInform Abstract Omeprazole (I) is transformed by gastric acid, producing a mixture of the isomeric thiadiazine derivatives (II).

Lipid nanoparticles (LNPs) are the most clinically advanced delivery system for RNA-based drugs but have predominantly been investigated for intravenous and intramuscular administration. Subcutaneous administration opens the possibility of patient self-administration and hence long-term chronic treatment that could enable messenger RNA (mRNA) to be used as a novel modality for protein replacement or regenerative therapies. In this study, we show that subcutaneous administration of mRNA formulated within LNPs can result in measurable plasma exposure of a secreted protein. However, subcutaneous administration of mRNA formulated within LNPs was observed to be associated with dose-limiting inflammatory responses. To overcome this limitation, we investigated the concept of incorporating aliphatic ester prodrugs of anti-inflammatory steroids within LNPs, i.e., functionalized LNPs to suppress the inflammatory response. We show that the effectiveness of this approach depends on the alkyl chain length of the ester prodrug, which determines its retention at the site of administration. An unexpected additional benefit to this approach is the prolongation observed in the duration of protein expression. Our results demonstrate that subcutaneous administration of mRNA formulated in functionalized LNPs is a viable approach to achieving systemic levels of therapeutic proteins, which has the added benefits of being amenable to self-administration when chronic treatment is required.

The previously determined crystal structure of the bacterial albumin‐binding GA module in complex with human serum albumin (HSA) suggested the possibility of utilizing the complex in the study of ligand binding to HSA. As a continuation of these studies, the crystal structure of the HSA–GA complex with the drug molecule naproxen and the fatty acid decanoate bound to HSA has been determined to a resolution of 2.5 Å. In terms of drug binding, the structure suggests that the binding of decanoate to the albumin molecule may play a role in making the haemin site in subdomain IB of the albumin molecule available for the binding of naproxen. In addition, structure comparisons with solved structures of HSA and of the HSA–GA complex show that the GA module is capable of binding to different conformations of HSA. The HSA–GA complex therefore emerges as a possible platform for the crystallographic study of specific HSA–drug interactions and of the influence exerted by the presence of fatty acids.

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