Jumping from Fragment to Drug via Smart Scaffolds.

A focused drug repurposing approach is described where an FDA-approved drug is rationally selected for biological testing based on structural similarities to a fragment compound found to bind a target protein by an NMR screen. The approach is demonstrated by first screening a curated fragment library using 19 F NMR to discover a quality binder to ACE2, the human receptor required for entry and infection by the SARS-CoV-2 virus. Based on this binder, a highly related scaffold was derived and used as a "smart scaffold" or template in a computer-aided finger-print search of a library of FDA-approved or marketed drugs. The most interesting structural match involved the drug vortioxetine which was then experimentally shown by NMR spectroscopy to bind directly to human ACE2. Also, an ELISA assay showed that the drug inhibits the interaction of human ACE2 to the SARS-CoV-2 receptor-binding-domain (RBD). Moreover, our cell-culture infectivity assay confirmed that vortioxetine is active against SARS-CoV-2 and inhibits viral replication. Thus, the use of "smart scaffolds" based on binders from fragment screens may have general utility for identifying candidates of FDA-approved or marketed drugs as a rapid repurposing strategy. Similar approaches can be envisioned for other fields involving small-molecule chemical applications.

Perfluorophenyl Derivatives as Unsymmetrical Linkers for Solid Phase Conjugation.

Linkers play major roles in conjugation chemistry toward the advancement of drug discovery. Two different series of fluorinated linkers were introduced to the backbone of a model peptide using solid phase peptide synthesis. These fluorinated linkers have the potential to conjugate two asymmetrical groups. This has not been done using other fluorinated linkers. This study deals with application of linkers with S, N, and O terminals and reports on the investigation of their chemoselectivity and activity for branching peptide backbones using a chosen model peptide. These fluorinated linkers have unique properties that will make it possible for a large diversity of bioconjugated chemicals for different bioapplications to be designed and synthesized.

Application of Decafluorobiphenyl (DFBP) Moiety as a Linker in Bioconjugation.

Considerable attention has been devoted to fluorinated compounds due to their unique and interesting properties. Many modern pharmaceuticals contain fluorinated substituents, which are commonly synthesized using selective fluorinating reagents. Decafluorobiphenyl (DFBP) as a fluorinated linker is susceptible to nucleophilic attack. This nucleophilic reaction has been widely studied using various nucleophiles. Sulfur and nitrogen containing nucleophiles have been of particular interest, especially in bioconjugated reactions. This review focuses on the SNAr reactivity of DFBP in formation of C-X (X = S, N) bonds, to be applied in bioconjugation in organic chemistry. The review aims to highlight the crucial factors that govern the chemistry behind the activation of F-CAr-CAr-F bonds as a linker in the synthesis of novel peptides, proteins, and biologics.

Organocatalyzed stereospecific C-C bond formation of ß-lactams.

Herein, we report the development of mild, organocatalyzed routes to novel carbapenam derivatives through aldol, Mannich and Michael C-C bond forming reactions.