Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation

The glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, detailed mechanistic understanding of how different peptides generate profound differences in G protein-mediated signalling is still lacking. Here we combine cryo-electron microscopy, molecular dynamics simulations, receptor mutagenesis and pharmacological assays, to interrogate the mechanism and consequences of GLP-1R binding to four peptide agonists; glucagon-like peptide-1, oxyntomodulin, exendin-4 and exendin-P5. These data reveal that distinctions in peptide N-terminal interactions and dynamics with the GLP-1R transmembrane domain are reciprocally associated with differences in the allosteric coupling to G proteins. In particular, transient interactions with residues at the base of the binding cavity correlate with enhanced kinetics for G protein activation, providing a rationale for differences in G protein-mediated signalling efficacy from distinct agonists

Activation of the GLP-1 receptor by a non-peptidic agonist

Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, including diabetes and obesity1. Structures of active receptors reveal peptide agonists engage deep within the receptor core, leading to an outward movement of extracellular loop 3 and the tops of transmembrane helices 6 and 7, an inward movement of transmembrane helix 1, reorganization of extracellular loop 2 and outward movement of the intracellular side of transmembrane helix 6, resulting in G-protein interaction and activation2,3,4,5,6. Here we solved the structure of a non-peptide agonist, TT-OAD2, bound to the glucagon-like peptide-1 (GLP-1) receptor. Our structure identified an unpredicted non-peptide agonist-binding pocket in which reorganization of extracellular loop 3 and transmembrane helices 6 and 7 manifests independently of direct ligand interaction within the deep transmembrane domain pocket. TT-OAD2 exhibits biased agonism, and kinetics of G-protein activation and signalling that are distinct from peptide agonists. Within the structure, TT-OAD2 protrudes beyond the receptor core to interact with the lipid or detergent, providing an explanation for the distinct activation kinetics that may contribute to the clinical efficacy of this compound series. This work alters our understanding of the events that drive the activation of class B receptors

Structure and Functions of Pediatric Aerodigestive Programs: A Consensus Statement

Aerodigestive programs provide coordinated interdisciplinary care to pediatric patients with complex congenital or acquired conditions affecting breathing, swallowing, and growth. Although there has been a proliferation of programs, as well as national meetings, interest groups and early research activity, there is, as of yet, no consensus definition of an aerodigestive patient, standardized structure, and functions of an aerodigestive program or a blueprint for research prioritization. The Delphi method was used by a multidisciplinary and multi-institutional panel of aerodigestive providers to obtain consensus on 4 broad content areas related to aerodigestive care: (1) definition of an aerodigestive patient, (2) essential construct and functions of an aerodigestive program, (3) identification of aerodigestive research priorities, and (4) evaluation and recognition of aerodigestive programs and future directions. After 3 iterations of survey, consensus was obtained by either a supermajority of 75% or stability in median ranking on 33 of 36 items. This included a standard definition of an aerodigestive patient, level of participation of specific pediatric disciplines in a program, essential components of the care cycle and functions of the program, feeding and swallowing assessment and therapy, procedural scope and volume, research priorities and outcome measures, certification, coding, and funding. We propose the first consensus definition of the aerodigestive care model with specific recommendations regarding associated personnel, infrastructure, research, and outcome measures. We hope that this may provide an initial framework to further standardize care, develop clinical guidelines, and improve outcomes for aerodigestive patients

Structure–activity study of N-((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652), a bitopic ligand that acts as a negative allosteric modulator of the dopamine D2 receptor

We recently demonstrated that SB269652 (1) engages one protomer of a dopamine D2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural deter- minants for allostery, focusing on modifications to three moieties within 1. We find that orthosteric “head” groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R “privileged structures” generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharma- cology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R

Comparative Treatment Outcomes for Patients With Idiopathic Subglottic Stenosis.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadImportance: Surgical treatment comparisons in rare diseases are difficult secondary to the geographic distribution of patients. Fortunately, emerging technologies offer promise to reduce these barriers for research. Objective: To prospectively compare the outcomes of the 3 most common surgical approaches for idiopathic subglottic stenosis (iSGS), a rare airway disease. Design, setting, and participants: In this international, prospective, 3-year multicenter cohort study, 810 patients with untreated, newly diagnosed, or previously treated iSGS were enrolled after undergoing a surgical procedure (endoscopic dilation [ED], endoscopic resection with adjuvant medical therapy [ERMT], or cricotracheal resection [CTR]). Patients were recruited from clinician practices in the North American Airway Collaborative and an online iSGS community on Facebook. Main outcomes and measures: The primary end point was days from initial surgical procedure to recurrent surgical procedure. Secondary end points included quality of life using the Clinical COPD (chronic obstructive pulmonary disease) Questionnaire (CCQ), Voice Handicap Index-10 (VHI-10), Eating Assessment Test-10 (EAT-10), the 12-Item Short-Form Version 2 (SF-12v2), and postoperative complications. Results: Of 810 patients in this cohort, 798 (98.5%) were female and 787 (97.2%) were white, with a median age of 50 years (interquartile range, 43-58 years). Index surgical procedures were ED (n = 603; 74.4%), ERMT (n = 121; 14.9%), and CTR (n = 86; 10.6%). Overall, 185 patients (22.8%) had a recurrent surgical procedure during the 3-year study, but recurrence differed by modality (CTR, 1 patient [1.2%]; ERMT, 15 [12.4%]; and ED, 169 [28.0%]). Weighted, propensity score-matched, Cox proportional hazards regression models showed ED was inferior to ERMT (hazard ratio [HR], 3.16; 95% CI, 1.8-5.5). Among successfully treated patients without recurrence, those treated with CTR had the best CCQ (0.75 points) and SF-12v2 (54 points) scores and worst VHI-10 score (13 points) 360 days after enrollment as well as the greatest perioperative risk. Conclusions and relevance: In this cohort study of 810 patients with iSGS, endoscopic dilation, the most popular surgical approach for iSGS, was associated with a higher recurrence rate compared with other procedures. Cricotracheal resection offered the most durable results but showed the greatest perioperative risk and the worst long-term voice outcomes. Endoscopic resection with medical therapy was associated with better disease control compared with ED and had minimal association with vocal function. These results may be used to inform individual patient treatment decision-making.Patient-Centered Outcomes Research Institute - PCOR

A Novel Endoscopic Arytenoid Medialization for Unilateral Vocal Fold Paralysis

Objectives/Hypothesis Arytenoid adduction (AA) has been indicated for unilateral vocal fold paralysis (UVFP) patients with vertical vocal fold height mismatch and/or large posterior glottic gaps that are unable to be adequately addressed by anterior medialization techniques. Although AA offers several advantages over other methods, it is technically challenging and involves significant laryngeal manipulation of the cricoarytenoid joint. A novel, minimally invasive endoscopic arytenoid medialization technique is presented for the closure of the posterior commissure. Study Design Prospective case series. Methods Seventeen consecutive patients were diagnosed and treated with unilateral endoscopic arytenoid medialization (EAM) combined with injection laryngoplasty because of unilateral vocal fold paralysis. Jitter, shimmer, harmonics-to-noise ratio (HNR), maximum phonation time (MPT), fundamental frequency (F-0), Voice Handicap Index (VHI), peak inspiratory flow (PIF), and quality of life (QoL) were evaluated preoperatively, 1 month, and 1 year after EAM. Results Jitter, shimmer, HNR, and MPT significantly improved and remained stable 1 year after the intervention. F(0)and PIF remained unchanged. Significant improvements in VHI and QoL demonstrated patient satisfaction with voicing and respiratory functions. Conclusions Endoscopic arytenoid medialization is a quick, minimally invasive solution for unilateral vocal fold paralysis. With simultaneous augmentation of the vocal fold, it provides a complete glottic closure along the entire vocal fold in UVFP patients. Level of Evidence 4Laryngoscope, 202

Endoscopic arytenoid abduction lateropexy for the treatment of neonatal bilateral vocal cord paralysis - Long-term results

Bilateral vocal cord paralysis often causes severe dyspnea requiring an early airway intervention in neonates. Endoscopic arytenoid abduction lateropexy (EAAL) with suture is a quick, reversible, minimally-invasive vocal cord lateralizing technique to enlarge the glottis. The arytenoid cartilage is directly lateralized to a normal abducted position. It can be performed even in early childhood with the recently-introduced pediatric endoscopic thread guide instrument. The long-term results and the stability of the lateralization were evaluated.Three newborns had inspiratory stridor immediately after birth. Laryngo-tracheoscopy revealed bilateral vocal cord paralysis. Unilateral, left-sided endoscopic arytenoid abduction lateropexy was performed with supraglottic jet ventilation. The follow-up period was >3 years.After extubation on the 4-7th postoperative day no dyspnea or swallowing disorder occurred. Laryngo-tracheoscopy, clinical growth charts and voice analysis showed satisfactory functional results.The endoscopic arytenoid abduction lateropexy might be a favorable solution for neonatal bilateral vocal cord paralysis. In one step, airway patency can be achieved without irreversible damage to the glottic structures. Normal swallowing function was preserved. The results are durable, and neither medialization nor dyspnea re-appeared during observation

Functional results of endoscopic arytenoid abduction lateropexy for bilateral vocal fold palsy

Endoscopic arytenoid abduction lateropexy (EAAL) is a reliable surgical solution for the minimally invasive treatment of bilateral vocal fold palsy (BVFP), providing a stable airway by the lateralization of the arytenoid cartilages with a simple suture. The nondestructive manner of the intervention theoretically leads to higher regeneration potential, thus better voice quality. The study aimed to investigate the respiratory and phonatory outcomes of this treatment concept.61 BVFP patients with significant dyspnea associated with thyroid/parathyroid surgery were treated by unilateral EAAL. Jitter, Shimmer, Harmonics to Noise Ratio, Maximum Phonation Time, Fundamental frequency, Voice Handicap Index, Dysphonia Severity Index, Friedrich's Dysphonia Index, Global-Roughness-Breathiness scale, Quality of Life, and Peak Inspiratory Flow were evaluated 18 months after EAAL.All patients had a stable and adequate airway during the follow-up. Ten patients (16.4%) experienced complete bilateral motion recovery with objective acoustic parameters in the physiological ranges. Most functional results of the 13 patients (21.3%) with unilateral recovery also reached the normal values. Fifteen patients (24.6%) had unilateral adduction recovery only, with slightly impaired voice quality. Eleven patients (18.0%) had false vocal fold phonation with socially acceptable voice. In 12 patients (19.7%) no significant motion recovery was detected on the glottic level.EAAL does not interfere with the potential regeneration process and meets the most important phoniatric requirements while guaranteeing the reversibility of the procedure-therefore serving patients with transient palsy. Further, a socially acceptable voice quality and an adequate airway are ensured even in cases of permanent bilateral vocal fold paralysis