Structure-Activity Relationships in Nucleotide Oligomerization Domain-1 (Nod1)-Agonistic γ-Glutamyl-diaminopimelic Acid Derivatives

N-acyl-γ-glutamyl-diaminopimelic acid is a prototype ligand for Nod1. We report a detailed SAR of C12-γ-D-Glu-DAP. Analogues with glutaric or γ-aminobutyric acid replacing the glutamic acid show greatly attenuated Nod1-agonistic activity. Substitution of the meso-diaminopimelic (DAP) acid component with monoaminopimelic acid, L- or D-lysine, or cadaverine also results in reduced activity. The free amine on DAP is crucial. However, the N-acyl group on the D-glutamyl residue can be substituted with N-alkyl groups with full preservation of activity. The free carboxylates on the DAP and Glu components can also be esterified, resulting in more lipophilic, but active analogues. Transcriptomal profiling showed a dominant upregulation of IL-19, IL-20, IL-22, and IL-24, which may explain the pronounced Th2-polarizing activity of these compounds, and also implicate cell signaling mediated by TREM-1. These results may explain the hitherto unknown mechanism of synergy between Nod1- and TLR-agonists, and are likely to be useful in designing vaccine adjuvants

Structure-Activity Relationships in Toll-like Receptor 2-Agonists Leading to Simplified Monoacyl Lipopeptides

Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM2CS) compounds are potential vaccine adjuvants. In continuation of previously reported structure-activity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C16) and an appropriately orientated ester carbonyl group is essential for TLR2-agonistic activity. The spacing between one of the palmitoyl ester carbonyl and the thioether is crucial to allow for an important H-bond, which observed in the crystal structure of the lipopeptide:TLR2 complex; consequently, activity is lost in homologated compounds. Penicillamine-derived analogues are also inactive, likely due to unfavorable steric interactions with the carbonyl of Ser 12 in TLR2. The thioether in this chemotype can be replaced with a selenoether. Importantly, the thioglycerol motif can be dispensed with altogether, and can be replaced with a thioethanol bridge. These results have led to a structurally simpler, synthetically more accessible, and water-soluble analogue possessing strong TLR2-agonistic activities in human blood

Impact of COVID-19 on gastroenterology fellowship training: a multicenter analysis of endoscopy volumes

Abstract Background and study aims The COVID-19 pandemic has had a profound impact on gastroenterology training programs. We aimed to objectively evaluate procedural training volume and impact of COVID-19 on gastroenterology fellowship programs in the United States. Methods This was a retrospective, multicenter study. Procedure volume data on upper and lower endoscopies performed by gastroenterology fellows was abstracted directly from the electronic medical record. The study period was stratified into 2 time periods: Study Period 1, SP1 (03/15/2020 to 06/30/2020) and Study Period 2, SP2 (07/01/2020 to 12/15/2020). Procedure volumes during SP1 and SP2 were compared to Historic Period 1 (HP1) (03/15/2019 to 06/30/2019) and Historic Period 2 (HP2) (07/01/2019 to 12/15/2019) as historical reference. Results Data from 23 gastroenterology fellowship programs (total procedures = 127,958) with a median of 284 fellows (range 273–289; representing 17.8 % of all trainees in the United States) were collected. Compared to HP1, fellows performed 53.6 % less procedures in SP1 (total volume: 28,808 vs 13,378; mean 105.52 ± 71.94 vs 47.61 ± 41.43 per fellow; P < 0.0001). This reduction was significant across all three training years and for both lower and upper endoscopies (P < 0.0001). However, the reduction in volume was more pronounced for lower endoscopy compared to upper endoscopy [59.03 % (95 % CI: 58.2–59.86) vs 48.75 % (95 % CI: 47.96–49.54); P < 0.0001]. The procedure volume in SP2 returned to near baseline of HP2 (total volume: 42,497 vs 43,275; mean 147.05 ± 96.36 vs 150.78 ± 99.67; P = 0.65). Conclusions Although there was a significant reduction in fellows’ endoscopy volume in the initial stages of the pandemic, adaptive mechanisms have resulted in a return of procedure volume to near baseline without ongoing impact on endoscopy training