New Generation Oxyntomodulin Peptides with Improved Pharmacokinetic Profiles Exhibit Weight Reducing and Anti-Steatotic Properties in Mice.

Oxyntomodulin (OXM) is an intestinal peptide hormone that activates both glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptors. The natural peptide reduces body weight in obese subjects and exhibits direct acute glucoregulatory effects in patients with type II diabetes. However, the clinical utility of OXM is limited due to its lower in vitro potency and short in vivo half-life. To overcome these issues, we developed stapled, long-acting, and highly potent OXM analogs with balanced activities at both GLP-1 and GCG receptors. The lead molecule O14 exhibits potent and long-lasting effects on glucose control, body weight loss, and reduction of hepatic fat reduction in DIO mice. Importantly, O14 significantly reversed hepatic steatosis; reduced liver weight, total cholesterol, and hepatic triglycerides; and improved markers of liver function in a nonalcoholic steatohepatitis (NASH) mouse model. A symmetrical version of the peptide was also shown to be more efficacious and long-lasting in controlling glucose than semaglutide and the clinical candidate cotadutide in wild-type mice, highlighting the utility of our designs of the dual agonist as a potential new therapy for diabetes and liver diseases.

Recombinant Expression and Stapling of a Novel Long-Acting GLP-1R Peptide Agonist.

Owing to their pleiotropic metabolic benefits, glucagon-like peptide-1 receptor (GLP-1R) agonists have been successfully utilized for treating metabolic diseases, such as type 2 diabetes and obesity. As part of our efforts in developing long-acting peptide therapeutics, we have previously reported a peptide engineering strategy that combines peptide side chain stapling with covalent integration of a serum protein-binding motif in a single step. Herein, we have used this strategy to develop a second generation extendin-4 analog rigidified with a symmetrical staple, which exhibits an excellent in vivo efficacy in an animal model of diabetes and obesity. To simplify the scale-up manufacturing of the lead GLP-1R agonist, a semisynthesis protocol was successfully developed, which involves recombinant expression of the linear peptide followed by attachment of a polyethylene glycol (PEG)-fatty acid staple in a subsequent chemical reaction step.

Design and Synthesis of Potent, Long-Acting Lipidated Relaxin-2 Analogs.

Peptide hormone relaxin-2, a member of the insulin family of peptides, plays a key role in hemodynamics and renal function and has shown preclinical efficacy in multiple disease models, including acute heart failure, fibrosis, preeclampsia, and corneal wound healing. Recently, serelaxin, a recombinant version of relaxin-2, has been studied in a large phase 3 clinical trial (RELAX-AHF-2) for acute decompensated heart failure patients with disappointing outcome. The poor in vivo half-life of relaxin-2 may have limited its therapeutic efficacy and long-term cardiovascular benefit. Herein, we have developed a semisynthetic methodology and generated potent, fatty acid-conjugated relaxin analogs with long-acting pharmacokinetic (PK) profile in rodents. The enhanced PK properties translated into improved and long-lasting pharmacodynamic effect in pubic ligament elongation (PLE) studies. The resultant novel relaxin analog, R9-13, represents the first long-acting relaxin-2 analog and could potentially improve the clinical efficacy and outcome for this important peptide hormone. This semisynthetic methodology could also be applied to other cysteine-rich peptides and proteins for half-life extension.

Transcription factor Nrf1 mediates the proteasome recovery pathway after proteasome inhibition in mammalian cells.

In Saccharomyces cerevisiae, chemical or genetic inhibition of proteasome activity induces new proteasome synthesis promoted by the transcription factor RPN4. This ensures that proteasome activity is matched to demand. This transcriptional feedback loop is conserved in mammals, but its molecular basis is not understood. Here, we report that nuclear factor erythroid-derived 2-related factor 1 (Nrf1), a transcription factor of the cap "n" collar basic leucine zipper family, but not the related Nrf2, is necessary for induced proteasome gene transcription in mouse embryonic fibroblasts (MEFs). Promoter-reporter assays revealed the importance of antioxidant response elements in Nrf1-mediated upregulation of proteasome subunit genes. Nrf1(-/-) MEFs were impaired in the recovery of proteasome activity after transient treatment with the covalent proteasome inhibitor YU101, and knockdown of Nrf1 in human cancer cells enhanced cell killing by YU101. Taken together, our results suggest that Nrf1-mediated proteasome homeostasis could be an attractive target for therapeutic intervention in cancer.

Minimal Detectable Change on the Lawton Instrumental Activities of Daily Living Scale in Community-Dwelling Patients With Schizophrenia.

The main purpose of this study was to estimate the minimal detectable change (MDC) on the Lawton Instrumental Activities of Daily Living (LIADL) scale in community-dwelling patients with schizophrenia. Fifty-seven patients completed the LIADL assessment twice, about 14 days apart. Two scoring methods (dichotomous and polytomous) were used to record the patients' performance on the LIADL scale. The MDCs of the LIADL scale were 1.5 (dichotomous) and 4.4 (polytomous) points. The MDC percentages were 22.0% (dichotomous) and 22.5% (polytomous), both of which are within acceptable measurement errors. The test-retest reliabilities of the LIADL scale were both acceptable with two different scoring methods (dichotomous = .75; polytomous = .76). Users can choose the scoring method according to their individual needs.

Loss of nuclear factor E2-related factor 1 in the brain leads to dysregulation of proteasome gene expression and neurodegeneration.

The ubiquitin-proteasome pathway plays an important role in the pathogenesis of neurodegeneration, but mechanisms controlling expression of components in this pathway remain poorly understood. Nuclear factor E2-related factor 1 (Nrf1) transcription factor has been shown to regulate expression of antioxidant and cytoprotective genes. To determine the function of Nrf1 in the brain, mice with a late-stage deletion of Nrf1 in neuronal cells were generated. Loss of Nrf1 leads to impaired proteasome function and neurodegeneration. Gene expression profiling and RT-PCR analysis revealed a coordinate down-regulation of various proteasomal genes including PsmB6, which encodes a catalytic subunit of the proteasome. Transcriptional analysis and chromatin immunoprecipitation experiments demonstrated that PsmB6 is an Nrf1 target gene. These findings reveal Nrf1 as a key transcriptional regulator required for the expression of proteasomal genes in neurons and suggest that perturbations of Nrf1 function may contribute to the pathogenesis of neurodegenerative diseases.

Access to Community Support Services among Older Adults in Social Housing in Ontario.

Community support services are an integral enabler of aging in place. In social housing, older adult tenants struggle to access these services because of the siloed nature of housing and health services. This study examined the provision of government-funded community support services to 83 seniors' social housing buildings in Toronto, Ontario. Although there were 56 different agencies operating within the buildings, only about one third of older tenants were actually receiving services. There was a subset of services that were available in more than 80 per cent of the buildings, and the most widely accessed services were food supports, crisis intervention, transportation, caregiver support, and hearing/vision care. There were also many cases in which multiple agencies offered duplicative services within the same building, suggesting that there are opportunities for improving service coordination. Practice recommendations for increasing access to community support services among low-income older adults in social housing are provided.

α/Sulfono-γ-AA peptide hybrids agonist of GLP-1R with prolonged action both in vitro and in vivo.

Peptides are increasingly important resources for biological and therapeutic development, however, their intrinsic susceptibility to proteolytic degradation represents a big hurdle. As a natural agonist for GLP-1R, glucagon-like peptide 1 (GLP-1) is of significant clinical interest for the treatment of type-2 diabetes mellitus, but its in vivo instability and short half-life have largely prevented its therapeutic application. Here, we describe the rational design of a series of α/sulfono-γ-AA peptide hybrid analogues of GLP-1 as the GLP-1R agonists. Certain GLP-1 hybrid analogues exhibited enhanced stability (t 1/2 > 14 days) compared to t 1/2 (<1 day) of GLP-1 in the blood plasma and in vivo. These newly developed peptide hybrids may be viable alternative of semaglutide for type-2 diabetes treatment. Additionally, our findings suggest that sulfono-γ-AA residues could be adopted to substitute canonical amino acids residues to improve the pharmacological activity of peptide-based drugs.

Design of Potent and Proteolytically Stable Biaryl-Stapled GLP-1R/GIPR Peptide Dual Agonists.

Recent clinical trials have revealed that the chimeric peptide hormones simultaneously activating glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) demonstrate superior efficacy in glycemic control and body weight reduction, better than those activating the GLP-1R alone. However, the linear peptide-based GLP-1R/GIPR dual agonists are susceptible to proteolytic cleavage by common digestive enzymes present in the gastrointestinal tract and thus not suitable for oral administration. Here, we report the design and synthesis of biaryl-stapled peptides, with and without fatty diacid attachment, that showed potent GLP-1R/GIPR dual agonist activities. Compared to a linear peptide dual agonist and semaglutide, the biaryl-stapled peptides displayed drastically improved proteolytic stability against the common digestive enzymes. Furthermore, two stapled peptides showed excellent efficacy in an oral glucose tolerance test in mice, owing to their potent receptor activity in vitro and good pharmacokinetics exposure upon subcutaneous injection. By exploring a more comprehensive set of biaryl staplers, we expect that this stapling method could facilitate the design of the stapled peptide-based dual agonists suitable for oral administration.

Deficiency in the nuclear factor E2-related factor-2 transcription factor results in impaired adipogenesis and protects against diet-induced obesity.

Nuclear factor E2-related factor 2 (Nrf2) is a cap-n-collar basic leucine zipper (CNC-bZIP) transcription factor that is well established as a master regulator of phase II detoxification and antioxidant gene expression and is strongly expressed in tissues involved in xenobiotic metabolism including liver and kidney. Nrf2 is also abundantly expressed in adipose tissue; however, the exact function of Nrf2 in adipocyte biology is unclear. In the current study we show that targeted knock-out of Nrf2 in mice decreases adipose tissue mass, promotes formation of small adipocytes, and protects against weight gain and obesity otherwise induced by a high fat diet. In mouse embryonic fibroblasts, 3T3-L1 cells, and human subcutaneous preadipocytes, selective deficiency of Nrf2 impairs adipocyte differentiation. Deficiency of Nrf2 also leads to decreased expression of peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT enhancer-binding protein alpha (C/EBPalpha), and their downstream targets during adipocyte differentiation. Conversely, activation of Nrf2 in 3T3-L1 cells by stable knockdown of its negative regulator Keap1 enhances and accelerates hormone-induced adipocyte differentiation. Transfection of Nrf2 stimulates Ppargamma promoter activity, and stable knockdown of Keap1 enhances PPARgamma expression in 3T3-L1 cells. In addition, chromatin immunoprecipitation studies show that Nrf2 associates with consensus binding sites for Nrf2 in the Ppargamma promoter. These findings demonstrate a novel biologic role for Nrf2 beyond its participation in detoxification and antioxidant pathways and place Nrf2 within the limited network of transcription factors that control adipocyte differentiation by regulating expression of PPARgamma.

Physical activity promotion: precise matching of message frames and affect types.

OBJECTIVE: Matching between affect orientations and message frames have been shown to enhance the persuasiveness of health messages. Based on a two-dimensional regulatory model (direction: approach/avoidance, valence: appetitive/aversive), this study examined whether a precise matching between affect and message frame would enhance physical activity (PA) attitudes, intentions, and behaviours. DESIGN: Using a 2 (gain/loss frames) x 2 (positive/negative end-states) design, 147 college students were randomly assigned to one message-frame condition (gain-positive, gain-negative, loss-positive, or loss-negative). Four identified affect types (approach-positive, approach-negative, avoidance-positive, and avoidance-negative) were considered as matched, respectively, with the four message-frame conditions. The participants were subsequently grouped into fully-matched, direction-matched only, valence-matched only, or unmatched. MAIN OUTCOME MEASURES: The immediate PA attitude and intention after the experiment and the PA attitudes, intentions, and behaviours at a two-week follow-up were reported. RESULTS: Post-manipulation and follow-up intentions were greater in the fully-matched as compared with the unmatched group. Follow-up physical activity was more in the valence-matched than the unmatched group. No other differences were found across the matching types. CONCLUSION: Findings partially supported the importance of a precise matching between affect orientations and message frames. The affect types may characterize an individual's sensitivity towards the corresponding regulatory information.

α/Sulfono-γ-AApeptide Hybrid Analogues of Glucagon with Enhanced Stability and Prolonged In Vivo Activity.

Peptide drugs have the advantages of target specificity and good drugability and have become one of the most increasingly important hotspots in new drug research in biomedical sciences. However, peptide drugs generally have low bioavailability and metabolic stability, and therefore, the modification of existing peptide drugs for the purpose of improving stability and retaining activity is of viable importance. It is known that glucagon is an effective therapy for treating severe hypoglycemia, but its short half-life prevents its wide therapeutic use. Herein, we report that combined unnatural residues and long fatty acid conjugation afford potent α/sulfono-γ-AApeptide hybrid analogues of Glucagon with enhanced stability and prolonged in vivo activity. This strategy could be adopted to develop stabilized analogues of other short-acting bioactive peptides.

Pharmacist- or Nurse Practitioner-Led Assessment and Titration of Sacubitril/Valsartan in a Heart Failure Clinic: A Cohort Study.

BACKGROUND: Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor indicated in the management of heart failure with reduced ejection fraction, based on the results of the PARADIGM-HF trial. Practice-based studies are needed to validate its effect in real-world settings. Clinical pharmacists are ideally situated to assess and titrate sacubitril/valsartan. OBJECTIVE: To evaluate the utilization, safety, and tolerability of sacubitril/valsartan in a multidisciplinary heart failure clinic, with assessment and titration by a clinical pharmacist or a nurse practitioner. METHODS: A retrospective cohort study was conducted at a heart failure clinic in Abbotsford, Canada. Included were adult patients with heart failure who were currently or formerly taking sacubitril/valsartan. Data collected for the period October 2015 to February 2019 included patient characteristics, New York Heart Association (NYHA) classification, concurrent medications, sacubitril/valsartan dose, adverse effects, and discontinuation rate. RESULTS: In total, 128 patients were included. Mean age was 70.1 years, 98 (77%) of the patients were men, and 79 (62%) had NYHA class 2 heart failure. The clinical pharmacist managed care for 78 (61%) of the patients, and the nurse practitioner managed care for 50 (39%). Forty-one (32%) of the patients met modified PARADIGM-HF inclusion criteria. Eighty-five (66%) of the patients achieved the target dose of sacubitril/valsartan, with similar proportions for the clinical pharmacist and nurse practitioner groups, over a mean of 2.2 clinic visits. Patients who achieved the sacubitril/valsartan target dose, relative to those who did not, were significantly younger and had higher mean systolic blood pressure at baseline. Twenty-nine percent of patients (35/119) had an improvement in NYHA classification from before initiation of sacubitril/valsartan to achievement of target or maximally tolerated dose. Eighty-five (66%) of the patients experienced an adverse effect, primarily hypotension, and 12 (9%) required a dose reduction. Only 9 (7%) patients discontinued therapy. CONCLUSIONS: This study demonstrates the real-world safety and tolerability of sacubitril/valsartan in the treatment of heart failure, and reinforces that clinical pharmacists can effectively assess and titrate medications in a multidisciplinary heart failure clinic.

CONTEXTE: Le sacubitril-valsartan est un inhibiteur novateur des récepteurs de l'angiotensine-néprilysine, indiqué dans la gestion de l'insuffisance cardiaque accompagnée d'une baisse de la fraction d'éjection, selon les résultats de l'essai PARADIGM-HF. Des études fondées sur la pratique sont nécessaires pour valider ses effets en contexte réel. Les pharmaciens cliniciens sont bien placés pour évaluer et titrer le sacubitril-valsartan. OBJECTIF: Évaluer l'utilisation, l'innocuité et le seuil de tolérance du sacubitril-valsartan en clinique multidisciplinaire d'insuffisance cardiaque, l'évaluation et le titrage étant effectués par un pharmacien clinicien ou une infirmière praticienne. MÉTHODES: Une étude de cohorte rétrospective a été menée au sein d'une clinique d'insuffisance cardiaque à Abbotsford, au Canada. Les patients adultes inclus dans l'étude souffraient d'insuffisance cardiaque, ils prenaient ou avaient pris du sacubitril-valsartan. Les données recueillies entre octobre 2015 et février 2019 comprenaient les caractéristiques des patients, la classification de la New York Heart Association (NYHA), les médicaments pris de façon concomitante, la dose de sacubitril-valsartan, les effets secondaires et le taux d'abandon. RÉSULTATS: Au total, 128 patients ont participé à l'étude. L'âge moyen des patients était de 70,1 ans, 98 d'entre eux (77 %) étaient des hommes et 79 (62 %) souffraient d'une insuffisance cardiaque de classe 2 selon la classification de la NYHA. Le pharmacien clinicien gérait les soins de 78 patients (61 %) et la pharmacienne praticienne gérait ceux de 50 patients (39 %). Quarante-et-un patients (32 %) répondaient aux critères d'inclusion modifiés de PARADIGM-HF. Quatre-vingt-cinq (66 %) patients atteignaient le dosage ciblé de sacubitril-valsartan dans des proportions similaires entre le groupe du pharmacien clinicien et celui de l'infirmière praticienne, à raison d'une moyenne de 2,2 visites en clinique. Les patients ayant atteint le dosage ciblé de sacubitril-valsartan, par rapport à ceux ne l'ayant pas atteint, étaient considérablement plus jeunes et leur tension artérielle systolique moyenne de base était plus élevée. Une amélioration de la classification NYHA a été observée chez 29 % des patients (35/119) entre le début de la prise de sacubitril-valsartan et l'atteinte du dosage ciblé ou de la dose maximale tolérée. Des effets secondaires ont été observés chez 85 patients (66 %), principalement une hypotension, et 12 d'entre eux (9 %) ont dû réduire la dose. Seuls 9 patients (7 %) ont dû abandonner la thérapie. CONCLUSIONS: Cette étude démontre l'innocuité et le seuil de tolérance en contexte réel du sacubitril-valsartan pour le traitement de l'insuffisance cardiaque. Elle renforce le fait que les pharmaciens cliniciens peuvent efficacement évaluer et titrer des médicaments au sein d'une clinique d'insuffisance cardiaque multidisciplinaire.

Survey of Drug Information Database Preferences among Staff from Selected British Columbia Health Authorities.

BACKGROUND: With the increasing use of electronic point-of-care resources, it is imperative to clearly understand what health professionals consider valuable when selecting a drug information database. A current analysis of the preferences of staff in selected British Columbia health authorities was deemed helpful for determining which electronic drug information database should be purchased. OBJECTIVES: To determine the factors that BC hospital pharmacists, nurses, and other health professionals value in an electronic drug information database and to better understand the general preferences of staff in choosing between the Lexicomp and Micromedex databases. METHODS: An electronic survey was created for data collection. The survey was open from August 10 to September 15, 2018, and again from November 11 to December 7, 2018. The survey link was sent by e-mail to staff in the following health authorities: Fraser Health, Providence Health Care, Provincial Health Services Authority, and Vancouver Coastal Health. Qualitative and quantitative methods were used to analyze the survey data. RESULTS: A total of 247 responses were received, of which 145 (58.7%) were complete. Completed surveys were received from 77 pharmacists, 52 nurses, and 16 other health professionals. Participants ranked dosing information and ease of use as the most important factors that they considered when choosing a drug information database. There were no significant differences between the Lexicomp and Micromedex resources in terms of usability, quality, and preference. CONCLUSIONS: This survey provided insights into what BC health authority staff perceive as important when utilizing a drug information database. Those considering either renewing or initiating a subscription to an online drug information database can use these results to better understand the preferences of health care professionals. Survey respondents ranked dosing information and ease of use as the 2 most important factors in selecting a drug information database. Pharmacists were more particular about using their preferred database than were other health professionals.

CONTEXTE: Avec l'utilisation croissante de ressources électroniques aux points de services, il est impératif de bien comprendre ce que les professionnels de la santé estiment important lorsqu'ils choisissent une base de données sur les médicaments. Une analyse actuelle des préférences des membres du personnel des autorités sanitaires sélectionnées de la Colombie-Britannique a été jugée utile pour déterminer le type de base de données sur les médicaments à acheter. OBJECTIFS: Déterminer quels facteurs sont importants pour les pharmaciens d'hôpitaux, les infirmiers et les autres professionnels de la santé de la C.-B. lors du choix d'une base de données électronique sur les médicaments et mieux cerner les préférences générales des membres du personnel lorsqu'ils choisissent entre les bases de données Lexicomp et Micromedex. MÉTHODES: Un sondage électronique a servi à la collecte des données. Il s'est déroulé du 10 août au 15 septembre 2018, et à nouveau du 11 novembre au 7 décembre 2018. Les membres du personnel des autorités sanitaires suivantes ont reçu le lien menant au sondage: Fraser Health, Providence Health Care, Provincial Health Services Authority et Vancouver Coastal Health. L'analyse des données a été effectuée à l'aide de méthodes qualitatives et quantitatives. RÉSULTATS: Les investigateurs ont reçu 247 réponses, dont 145 étaient complètes (58,7 %). Soixante-dix-sept (77) pharmaciens, 52 infirmiers et 16 autres professionnels de la santé ont dument rempli le sondage. Les participants ont indiqué que les renseignements sur le dosage et la facilité d'utilisation étaient les deux facteurs les plus importants à prendre en compte lors du choix d'une base de données sur les médicaments. Aucune différence significative n'est ressortie entre les bases de données Lexicomp et Micromedex quant à l'opérabilité, la qualité et la préférence. CONCLUSIONS: Ce sondage a permis de fournir un aperçu sur ce que les membres du personnel des autorités sanitaires de la C.-B. percevaient comme important pour l'utilisation d'une base de données sur les médicaments. Les personnes qui ont l'intention de renouveler ou de souscrire un abonnement à une base de données sur les médicaments en ligne peuvent utiliser ces résultats pour mieux cerner les préférences des professionnels de la santé. Les répondants ont indiqué que les renseignements sur le dosage et la facilité d'utilisation étaient les deux facteurs les plus importants à prendre en compte lors du choix d'une base de données sur les médicaments. Les pharmaciens étaient moins disposés que les autres professionnels de la santé à changer leur base de données préférée pour une autre.

Effect of Warming on Growth, Grazing, and Community Composition of Free-Living Bacterioplankton in Subtropical Coastal Waters During Winter and Summer.

Global warming is considered a major threat to marine ecosystems, which affects bacterioplankton activity, diversity, and community composition. However, few studies focus on the potential effects of warming on bacterioplankton in subtropical coastal waters in different seasons. Here we investigated the influences of warming on growth, grazing and community composition of bacterioplankton in Hong Kong coastal waters during winter and summer via 1-day incubation experiments. Our results revealed that without grazers, bacterioplankton displayed higher growth rate during summer compared to winter, while warming only significantly increased the growth rate of bacterioplankton in winter. Grazers with size <5 µm were major predators of bacterioplankton. Warming had little effect on grazing in summer but significantly enhanced grazing rates of >5 µm grazers in winter. In both seasons, warming had little influence on bacterial diversity and community composition. Nevertheless, in family and OTU levels, bacterioplankton had different responses to grazing and warming which may result from the selective grazing preference of predators and different temperature optima for bacterioplankton. Furthermore, the presence of >5 µm and <5 µm grazers would result in significant increase of some bacterial families under warming condition. Together, our results suggest that warming have direct impacts on bacterioplankton in subtropical coastal waters during winter and may thus affect global biogeochemical cycles.

Engineering a Potent, Long-Acting, and Periphery-Restricted Oxytocin Receptor Agonist with Anorexigenic and Body Weight Reducing Effects.

The effects of oxytocin on food intake and body weight reduction have been demonstrated in both animal models and human clinical studies. Despite being efficacious, oxytocin is enzymatically unstable and thus considered to be unsuitable for long-term use in patients with obesity. Herein, a series of oxytocin derivatives were engineered through conjugation with fatty acid moieties that are known to exhibit high binding affinities to serum albumin. One analog (OT-12) in particular was shown to be a potent full agonist at the oxytocin receptor (OTR) in vitro with good selectivity and long half-life (24 h) in mice. Furthermore, OT-12 is peripherally restricted, with very limited brain exposure (1/190 of the plasma level). In a diet-induced obesity mouse model, daily subcutaneous administration of OT-12 exhibited more potent anorexigenic and body weight reducing effects than carbetocin. Thus, our results suggest that the long-acting, peripherally restricted OTR agonist may offer potential therapeutic benefits for obesity.

The activity of sulfono-γ-AApeptide helical foldamers that mimic GLP-1.

Existing long α-helix mimicking necessitates the retention of most natural amino acid residues to maintain their biological activity. Here, we report the exploration of helical sulfono-γ-AApeptides with entire unnatural backbones for their ability to structurally and functionally mimic glucagon-like peptide 1 (GLP-1). Our findings suggest that efficient construction of novel GLP-1 receptor (GLP-1R) agonists could be achieved with nanomolar potencies. In addition, the resulting sulfono-γ-AApeptides were also proved to display remarkable stability against enzymatic degradation compared to GLP-1, augmenting their biological potential. This alternative strategy of α-helix mimicking, as a proof of concept, could provide a new paradigm to prepare GLP-1R agonists.

Design of a Long-Acting and Selective MEG-Fatty Acid Stapled Prolactin-Releasing Peptide Analog.

Anorexigenic peptides offer promise as potential therapies targeting the escalating global obesity epidemic. Prolactin-releasing peptide (PrRP), a novel member of the RFamide family secreted by the hypothalamus, shows therapeutic potential by decreasing food intake and body weight in rodent models via GPR10 activation. Here we describe the design of a long-acting PrRP using our recently developed novel multiple ethylene glycol-fatty acid (MEG-FA) stapling platform. By incorporating serum albumin binding fatty acids onto a covalent side chain staple, we have generated a series of MEG-FA stapled PrRP analogs with enhanced serum stability and in vivo half-life. Our lead compound 18-S4 exhibits good in vitro potency and selectivity against GPR10, improved serum stability, and extended in vivo half-life (7.8 h) in mouse. Furthermore, 18-S4 demonstrates a potent body weight reduction effect in a diet-induced obesity (DIO) mouse model, representing a promising long-acting PrRP analog for further evaluation in the chronic obesity setting.

Nrf1 and Nrf2 regulate rat glutamate-cysteine ligase catalytic subunit transcription indirectly via NF-kappaB and AP-1.

Glutamate-cysteine ligase catalytic subunit (GCLC) is regulated transcriptionally by Nrf1 and Nrf2. tert-Butylhydroquinone (TBH) induces human GCLC via Nrf2-mediated trans activation of the antioxidant-responsive element (ARE). Interestingly, TBH also induces rat GCLC, but the rat GCLC promoter lacks ARE. This study examined the role of Nrf1 and Nrf2 in the transcriptional regulation of rat GCLC. The baseline and TBH-mediated increase in GCLC mRNA levels and rat GCLC promoter activity were lower in Nrf1 and Nrf2 null (F1 and F2) fibroblasts than in wild-type cells. The basal protein and mRNA levels and nuclear binding activities of c-Jun, c-Fos, p50, and p65 were lower in F1 and F2 cells and exhibited a blunted response to TBH. Lower c-Jun and p65 expression also occurs in Nrf2 null livers. Levels of other AP-1 and NF-kappaB family members were either unaffected (i.e., JunB) or increased (i.e., Fra-1). Overexpression of Nrf1 and Nrf2 in respective cells restored the rat GCLC promoter activity and response to TBH but not if the AP-1 and NF-kappaB binding sites were mutated. Fra-1 overexpression lowered endogenous GCLC expression and rat GCLC promoter activity, while Fra-1 antisense had the opposite effects. In conclusion, Nrf1 and Nrf2 regulate rat GCLC promoter by modulating the expression of key AP-1 and NF-kappaB family members.

Stapled, Long-Acting Glucagon-like Peptide 2 Analog with Efficacy in Dextran Sodium Sulfate Induced Mouse Colitis Models.

Glucagon-like peptide 2 (GLP-2) is a hormone that has been shown to stimulate intestinal growth and attenuate intestinal inflammation. Despite being efficacious in a variety of animal models of disease, its therapeutic potential is hampered by the short half-life in vivo. We now describe a highly potent, stapled long-acting GLP-2 analog, peptide 10, that has a more than 10-fold longer half-life than teduglutide and improved intestinotrophic and anti-inflammatory effects in mouse models of DSS-induced colitis.