Notes

Controversies throughout EUS: Can we need miniprobes?
The anaerobic conversion of choline to trimethylamine (TMA) by the human gut microbiota has been linked to multiple human diseases. The potential impact of this microbial metabolic activity on host health has inspired multiple efforts to identify small molecule inhibitors. Here, we use information about the structure and mechanism of the bacterial enzyme choline TMA-lyase (CutC) to develop a cyclic choline analog that inhibits the conversion of choline to TMA in bacterial whole cells and in a complex gut microbial community. In vitro biochemical assays and a crystal structure suggest that this analog is a competitive, mechanism-based inhibitor. This work demonstrates the utility of structure-based design to access inhibitors of radical enzymes from the human gut microbiota.Tafamidis, 1, a potent transthyretin kinetic stabilizer, weakly inhibits the γ-secretase enzyme in vitro. We have synthesized four amide derivatives of 1. These compounds reduce production of the Aβ peptide in N2a695 cells but do not inhibit the γ-secretase enzyme in cell-free assays. By performing fluorescence correlation spectroscopy, we have shown that TTR inhibits Aβ oligomerization and that addition of tafamidis or its amide derivative does not affect TTR's ability to inhibit Aβ oligomerization. The piperazine amide derivative of tafamidis (1a) efficiently penetrates and accumulates in mouse brain and undergoes proteolysis under physiological conditions in mice to produce tafamidis.The design, synthesis, biological evaluation, and X-ray structural studies are reported for a series of highly potent HIV-1 protease inhibitors. The inhibitors incorporated stereochemically defined amide-based bicyclic and tricyclic ether derivatives as the P2 ligands with (R)-hydroxyethylaminesulfonamide transition-state isosteres. A number of inhibitors showed excellent HIV-1 protease inhibitory and antiviral activity; however, ligand combination is critical for potency. Inhibitor 4h with a difluorophenylmethyl as the P1 ligand, crown-THF-derived acetamide as the P2 ligand, and a cyclopropylaminobenzothiazole P2'-ligand displayed very potent antiviral activity and maintained excellent antiviral activity against selected multidrug-resistant HIV-1 variants. A high resolution X-ray structure of inhibitor 4h-bound HIV-1 protease provided molecular insight into the binding properties of the new inhibitor.In this study, starting from our selective D3R agonist FOB02-04A (5), we investigated the chemical space around the linker portion of the molecule via insertion of a hydroxyl substituent and ring-expansion of the trans-cyclopropyl moiety into a trans-cyclohexyl scaffold. Moreover, to further elucidate the importance of the primary pharmacophore stereochemistry in the design of bitopic ligands, we investigated the chiral requirements of (+)-PD128907 ((+)-(4aR,10bR)-2)) by synthesizing and resolving bitopic analogues in all the cis and trans combinations of its 9-methoxy-3,4,4a,10b-tetrahydro-2H,5H-chromeno[4,3-b][1,4] oxazine scaffold. Despite the lack of success in obtaining new analogues with improved biological profiles, in comparison to our current leads, a "negative" result due to a poor or simply not improved biological profile is fundamental toward better understanding chemical space and optimal stereochemistry for target recognition. Herein, we identified essential structural information to understand the differences between orthosteric and bitopic ligand-receptor binding interactions, discriminate D3R active and inactive states, and assist multitarget receptor recognition. Exploring stereochemical complexity and developing extended D3R SAR from this new library complements previously described SAR and inspires future structural and computational biology investigation. Moreover, the expansion of chemical space characterization for D3R agonism may be utilized in machine learning and artificial intelligence (AI)-based drug design, in the future.Aminotransferases are pyridoxal 5'-phosphate-dependent enzymes that catalyze reversible transamination reactions between an amino acid and an α-keto acid, playing a critical role in cellular nitrogen metabolism. It is evident that γ-aminobutyric acid aminotransferase (GABA-AT), which balances the levels of inhibitory and excitatory neurotransmitters, has emerged as a promising therapeutic target for epilepsy and cocaine addiction based on mechanism-based inactivators (MBIs). In this work, we established an integrated approach using computational simulation, organic synthesis, biochemical evaluation, and mass spectrometry to facilitate our design and mechanistic studies of MBIs, which led to the identification of a new cyclopentene-based analogue (6a), 25-times more efficient as an inactivator of GABA-AT compared to the parent compound (1R,3S,4S)-3-amino-4-fluorocyclopentane carboxylic acid (FCP, 4).The melanocortin receptors are involved in numerous physiological functions and are regulated by agonists derived from the proopiomelanocortin gene transcript and two endogenous antagonists, agouti and agouti-related protein (AGRP). The key binding and functional determinant of AGRP, an MC3R and MC4R antagonist, is an Arg-Phe-Phe tripeptide sequence located on an exposed hexapeptide (Arg-Phe-Phe-Asn-Ala-Phe) loop. AM580 datasheet It has previously been observed that cyclizing this sequence through a DPro-Pro motif (c[Pro1-Arg2-Phe3-Phe4-Asn5-Ala6-Phe7-DPro8]) resulted in a macrocyclic scaffold with MC4R antagonist activity, with increased MC4R potency when a diaminopropionic acid (Dap) residue is substituted at position 5. In this report, a series of 11 single-peptoid substitutions were performed in the AGRP-derived macrocycles. While most peptoid substitutions decreased MC4R antagonist potency, it was observed that NPhe4 (compounds 4 and 11) or NDab5 (diaminobutyric acid, compound 7) maintained MC4R antagonist potency. The NPhe4 substitutions also resulted in MC5R antagonist and inverse agonist activity equipotent to the parent scaffolds. These data may be used in the design of future MC4R and MC5R antagonist leads and probes that possess increased metabolic stability due to the presence of peptoid residues.
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