Peptide-based Molecules Research Articles

Real-World Effectiveness of Oral Semaglutide in Indian Adult Diabetic Patients: Evaluation of EMR-based Data

Abstract Introduction: Diabetes is increasingly becoming a significant health concern globally, including in India, where its prevalence continues to increase. Being overweight often acts as a catalyst for developing diabetes, exacerbating the condition and increasing the risk of other serious health complications such as heart disease, kidney problems, and nerve damage. Peptide-based molecules like semaglutide have proved their efficacy in controlling glycated hemoglobin (HbA1c) levels and body weight in diabetic patients. Objective: The present study aims to determine the effectiveness of oral semaglutide in a real-world setting. Materials and Methods: This retrospective study included patients ≥18 years of age prescribed oral semaglutide with a follow-up visit between 80 and 160 days post-prescription and had baseline body mass index (BMI) ≥ 30 kg/m2 and HbA1c levels ≤10.0%. The primary endpoints were to assess changes in HbA1c level, BMI, and body weight from the baseline. The secondary endpoints were to determine the changes in postprandial blood sugar (PPBS), fasting blood sugar (FBS), and blood pressure. The analysis also encompassed data on comorbid conditions and concomitant medications prescribed. Results: A total of 188 patients met the study eligibility criteria. At the follow-up visit, a statistically significant mean reduction of 0.34% in HbA1c levels and a weight loss of 1.83 kg were observed. The average duration between baseline and follow-up visit was 114.14 ± 21.5 days. The mean reduction in the BMI was 0.73 kg/m2 (P < 0.001). During the follow-up visit, the PPBS level decreased by 9.95 mg/dL and the FBS level decreased by 5.02 mg/dL. Additionally, the effect of semaglutide on blood pressure was evident, with a reduction in systolic blood pressure by 1.69 mm Hg and diastolic blood pressure by 1.30 mm Hg. The most common comorbid condition was dyslipidemia (66.49%), followed by hypertension (51.60%) and obesity (39.36%). Conclusion: Semaglutide demonstrated significant reductions in glycemic parameters, body weight, and blood pressure.

Peptides for Targeting Chondrogenic Induction and Cartilage Regeneration in Osteoarthritis.

Osteoarthritis (OA) is a widespread degenerative joint condition commonly occurring in older adults. Currently, no disease-modifying drugs are available, and safety concerns associated with commonly used traditional medications have been identified. In this review, a significant portion of research in this field is concentrated on cartilage, aiming to discover methods to halt cartilage breakdown or facilitate cartilage repair. Researchers have mainly investigated the cartilage, seeking methods to promote its repair. This review focuses on peptide-based molecules known for their ability to selectively bind to growth factor cytokines and components of the cartilage extracellular matrix. Chondroinductive peptides, synthetically producible, boast superior reproducibility, stability, modifiability, and yield efficiency over natural biomaterials. This review outlines a chondroinductive peptide design, molecular mechanisms, and their application in cartilage tissue engineering and also compares their efficacy in chondrogenesis in vitro and in vivo. In this paper, we will summarize the application of peptides engineered to regenerate cartilage by acting as scaffolds, functional molecules, or both and discuss additional possibilities for peptides. This review article provides an overview of our current understanding of chondroinductive peptides for treating OA-affected cartilage and explores the delivery systems used for regeneration. These advancements may hold promise for enhancing or even replacing current treatment methodologies.

Lysine-based non-cytotoxic ultrashort self-assembling peptides with antimicrobial activity.

Peptide-based molecules and their hydrogels are useful materials for biomedical applications due to the reversible nature of their self-assembly as well as the diversity of nanostructures that can be created starting from low-molecular weight compounds. In this study, we have focused on comprehending the characteristics of fibrillar networks of l-lysine-based self-assembled dipeptide hydrogels with a focus on their antibacterial properties. For that purpose, l-lysine has been complemented with hydrophobic aromatic moieties coming from l-phenylalanine and benzyloxyxarbonyl N-capping. In addition, the peptide C-terminus is blocked with alkylamides of different chain lengths which introduces additional dispersive interactions and hydrophobicity. These materials were well characterized by transmission electron microscopy, scanning electron microscopy, wide-angle powder X-ray diffraction and oscillatory rheology. Finally, biocompatibility and antimicrobial tests were performed showing that these hydrogels are compatible with HEK 293 cells and present a remarkable antibacterial activity against both Gram positive (S. aureus) and Gram negative (E. coli) bacteria.

A library-derived peptide inhibitor of the BZLF1 transcription factor.

Transcription factor dysregulation is associated with many diseases, including cancer. Peptide-based molecules are increasingly recognised as important modulators of difficult intracellular protein-protein interaction targets, with peptide library screening consequently proven to be a viable strategy in developing inhibitors against a wide range of transcription factors (TFs). However, current strategies simply select the highest affinity of binding to a target TF rather than the ability to inhibit TF function. Here, we utilise our Transcription Block Survival (TBS) screening platform to enable high-throughput identification of peptides that inhibit TFs from binding to cognate DNA sites, hence inhibiting functionality. In this study, we explore whether the TBS can be expanded to derive a potent and functional peptide inhibitor of the BZLF1 transcription factor. The library-derived peptide, AcidicW, is shown to form a more stable dimer with BZLF1 than the BZLF1 homodimer, with a thermal denaturation temperature exceeding 80°C. AcidicW can also functionally inhibit the BZLF1:TRE DNA interaction with high potency and an IC50 of 612 nM.

Differential specificity of SARS-CoV-2 main protease variants on peptide versus protein-based substrates.

The SARS-CoV-2 main protease (Mpro ) holds significant importance as a biological target in combating coronaviruses due to its importance in virus replication. Considering the emergence of novel SARS-CoV-2 variants and the mutations observed in the Mpro sequence, we hypothesized that these mutations may have a potential impact on the protease's specificity. To test this, we expressed Mpro corresponding to the original strain and variants Beta1, Beta2, and Omicron and analyzed their activity on protein-based and peptide substrates. Although we observed differential activity on the protein-based substrate, there was very little difference when analyzed on the peptide substrate. We conclude that mutations on the Mpro sequence, despite having a minor effect on a peptide substrate cleavage, did not change the catalytic site environment enough to build resistance to inhibition. Therefore, we propose that inhibitors initially designed for the Mpro of the original strain will be effective in all the variants. Thus, Mpro is likely to continue to be a target of therapeutic interest as mutations in its sequence are rare and, as we show here, have a minor effect on the protease's recognition of peptide-based molecules.

β-Turn Induction by a Diastereopure Azepane-Derived Quaternary Amino Acid.

β-Turns are one of the most common secondary structures found in proteins. In the interest of developing novel β-turn inducers, a diastereopure azepane-derived quaternary amino acid has been incorporated into a library of simplified tetrapeptide models in order to assess the effect of the azepane position and peptide sequence on the stabilization of β-turns. The conformational analysis of these peptides by molecular modeling, NMR spectroscopy, and X-ray crystallography showed that this azepane amino acid is an effective β-turn inducer when incorporated at the i + 1 position. Moreover, the analysis of the supramolecular self-assembly of one of the β-turn-containing peptide models in the solid state reveals that it forms a supramolecular helical arrangement while maintaining the β-turn structure. The results here presented provide the basis for the use of this azepane quaternary amino acid as a strong β-turn inducer in the search for novel peptide-based bioactive molecules, catalysts, and biomaterials.

Discovery of an orally effective double-stapled peptide for reducing ovariectomy-induced bone loss in mice.

Stapled peptides with significantly enhanced pharmacological profiles have emerged as promising therapeutic molecules due to their remarkable resistance to proteolysis and performance to penetrate cells. The all-hydrocarbon peptide stapling technique has already widely adopted with great success, yielding numerous potent peptide-based molecules. Based on our prior efforts, we conceived and prepared a double-stapled peptide in this study, termed FRNC-1, which effectively attenuated the bone resorption capacity of mature osteoclasts invitro through specific inhibition of phosphorylated GSK-3β. The double-stapled peptide FRNC-1 displayed notably improved helical contents and resistance to proteolysis than its linear form. Additionally, FRNC-1 effectively prevented osteoclast activation and improved bone density for ovariectomized (OVX) mice after intravenous injection and importantly, after oral (intragastric) administration. The double-stapled peptide FRNC-1 is the first orally effective peptide that has been validated to date as a therapeutic candidate for postmenopausal osteoporosis (PMOP).

BinderSpace: A package for sequence space analyses for datasets of affinity-selected oligonucleotides and peptide-based molecules.

Discovery of target-binding molecules, such as aptamers and peptides, is usually performed with the use of high-throughput experimental screening methods. These methods typically generate large datasets of sequences of target-binding molecules, which can be enriched with high affinity binders. However, the identification of the highest affinity binders from these large datasets often requires additional low-throughput experiments or other approaches. Bioinformatics-based analyses could be helpful to better understand these large datasets and identify the parts of the sequence space enriched with high affinity binders. BinderSpace is an open-source Python package that performs motif analysis, sequence space visualization, clustering analyses, and sequence extraction from clusters of interest. The motif analysis, resulting in text-based and visual output of motifs, can also provide heat maps of previously measured user-defined functional properties for all the motif-containing molecules. Users can also run principal component analysis (PCA) and t-distributed stochastic neighbor embedding (t-SNE) analyses on whole datasets and on motif-related subsets of the data. Functionally important sequences can also be highlighted in the resulting PCA and t-SNE maps. If points (sequences) in two-dimensional maps in PCA or t-SNE space form clusters, users can perform clustering analyses on their data, and extract sequences from clusters of interest. We demonstrate the use of BinderSpace on a dataset of oligonucleotides binding to single-wall carbon nanotubes in the presence and absence of a bioanalyte, and on a dataset of cyclic peptidomimetics binding to bovine carbonic anhydrase protein. BinderSpace is openly accessible to the public via the GitHub website: https://github.com/vukoviclab/BinderSpace.

Structure-activity relationships of antibacterial peptides.

Antimicrobial peptides play a crucial role in innate immunity, whose components are mainly peptide-based molecules with antibacterial properties. Indeed, the exploration of the immune system over the past 40 years has revealed a number of natural peptides playing a pivotal role in the defence mechanisms of vertebrates and invertebrates, including amphibians, insects, and mammalians. This review provides a discussion regarding the antibacterial mechanisms of peptide-based agents and their structure-activity relationships (SARs) with the aim of describing a topic that is not yet fully explored. Some growing evidence suggests that innate immunity should be strongly considered for the development of novel antibiotic peptide-based libraries. Also, due to the constantly rising concern of antibiotic resistance, the development of new antibiotic drugs is becoming a priority of global importance. Hence, the study and the understanding of defence phenomena occurring in the immune system may inspire the development of novel antibiotic compound libraries and set the stage to overcome drug-resistant pathogens. Here, we provide an overview of the importance of peptide-based antibacterial sources, focusing on accurately selected molecular structures, their SARs including recently introduced modifications, their latest biotechnology applications, and their potential against multi-drug resistant pathogens. Last, we provide cues to describe how antibacterial peptides show a better scope of action selectivity than several anti-infective agents, which are characterized by non-selective activities and non-targeted actions toward pathogens.

In silico design of photoresponsive peptide-based hydrogel with controllable structural and rheological properties

Self-assembly of peptide-based molecules has emerged as an appealing strategy for developing intelligent nanomaterials with favorable biocompatibility and biodegradability. However, how to design the self-assembly systems with controllable and reversible rheological property is still challenging. In this study, coarse-grained molecular dynamics simulation is employed to develop peptides-based hydrogel with photo-stimuli-responsive capability. Our simulations demonstrate that the bisazoFA molecule, generated by grafting azobenzene (azo) moiety to the phenylalanyl-alanine (FA), can self-assemble into twisted networks. With the introduction of diphenylalanine (FF), the micelles undergo morphological transitions from networks to lamellar structures. By manipulating the UV–vis light irradiation, the wormlike structure with orderly-arranged hydrophobic interior is achieved. The distinct self-assembled structures can induce varied viscosity. Furthermore, the mechanisms underlying the self-assembly/stimuli-response processes are examined in the perspective from energy and structure. Specifically, the varied structural/rheological property of systems are driven by the stacking modes between bisazoFA and spatial arrangement of FF molecules. This bottom-up in silico design not only offers a feasible strategy to develop hydrogel with controllable and reversible rheological property, but also enrich our understanding of the self-assembly of peptide-based molecules.

Dengue, West Nile, and Zika Viruses: Potential Novel Antiviral Biologics Drugs Currently at Discovery and Preclinical Development Stages.

Dengue, West Nile and Zika viruses are vector-borne flaviviruses responsible for numerous disease outbreaks in both Hemispheres. Despite relatively low mortality, infection may lead to potentially severe situations such as (depending on the virus): hypovolemic shock, encephalitis, acute flaccid paralysis, Guillain-Barré syndrome, congenital malformations (e.g., microcephaly) and, in some situations, death. Moreover, outbreaks also have major socioeconomic repercussions, especially in already vulnerable societies. Thus far, only generic symptoms relief is possible, as there are no specific treatments available yet. Dengvaxia was the world's first dengue vaccine. However, it is not fully effective. Prophylactic approaches against West Nile and Zika viruses are even more limited. Therefore, therapeutic strategies are required and will be discussed hereafter. We will first briefly present these viruses' epidemiology, life cycle and structure. Then, we introduce the clinical presentation, diagnosis approaches and available vaccines. Finally, we list and discuss promising compounds at discovery and preclinical development stages already deposited at the GlobalData database and divided into three main types, according to therapeutic molecule: antibody-based, peptide-based molecules and, other compounds. To conclude, we discuss and compare promising developments, useful for future therapies against these three flaviviruses of major concern to human health.

Can machine learning 'transform' peptides/peptidomimetics into small molecules? A case study with ghrelin receptor ligands.

There has been considerable interest in transforming peptides into small molecules as peptide-based molecules often present poorer bioavailability and lower metabolic stability. Our studies looked into building machine learning (ML) models to investigate if ML is able to identify the 'bioactive' features of peptides and use the features to accurately discriminate between binding and non-binding small molecules. The ghrelin receptor (GR), a receptor that is implicated in various diseases, was used as an example to demonstrate whether ML models derived from a peptide library can be used to predict small molecule binders. ML models based on three different algorithms, namely random forest, support vector machine, and extreme gradient boosting, were built based on a carefully curated dataset of peptide/peptidomimetic and small molecule GR ligands. The results indicated that ML models trained with a dataset exclusively composed of peptides/peptidomimetics provide limited predictive power for small molecules, but that ML models trained with a diverse dataset composed of an array of both peptides/peptidomimetics and small molecules displayed exceptional results in terms of accuracy and false rates. The diversified models can accurately differentiate the binding small molecules from non-binding small molecules using an external validation set with new small molecules that we synthesized previously. Structural features that are the most critical contributors to binding activity were extracted and are remarkably consistent with the crystallography and mutagenesis studies.

Short Peptides and Their Mimetics as Potent Antibacterial Agents and Antibiotic Adjuvants.

Antimicrobial resistance (AMR) has been increasing unrelentingly worldwide, thus negatively impacting human health. The discovery and development of novel antibiotics is an urgent unmet need of the hour. However, it has become more challenging, requiring increasingly time-consuming efforts with increased commercial risks. Hence, alternative strategies are urgently needed to potentiate the existing antibiotics. In this context, short cationic peptides or peptide-based antimicrobials that mimic the activity of naturally occurring antimicrobial peptides (AMPs) could overcome the disadvantages of AMPs having evolved as potent antibacterial agents. Besides their potent antibacterial efficacy, short peptide conjugates have also gained attention as potent adjuvants to conventional antibiotics. Such peptide antibiotic combinations have become an increasingly cost-effective therapeutic option to tackle AMR. This Review summarizes the recent progress for peptide-based small molecules as promising antimicrobials and as adjuvants for conventional antibiotics to counter multidrug resistant (MDR) pathogens.

Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting Its Protein-Protein Interactions.

We developed a new class of inhibitors of protein–protein interactions of the SHP2 phosphatase, which is pivotal in cell signaling and represents a central target in the therapy of cancer and rare diseases. Currently available SHP2 inhibitors target the catalytic site or an allosteric pocket but lack specificity or are ineffective for disease-associated SHP2 mutants. Considering that pathogenic lesions cause signaling hyperactivation due to increased levels of SHP2 association with cognate proteins, we developed peptide-based molecules with nanomolar affinity for the N-terminal Src homology domain of SHP2, good selectivity, stability to degradation, and an affinity for pathogenic variants of SHP2 that is 2–20 times higher than for the wild-type protein. The best peptide reverted the effects of a pathogenic variant (D61G) in zebrafish embryos. Our results provide a novel route for SHP2-targeted therapies and a tool for investigating the role of protein–protein interactions in the function of SHP2.

The Current Status of Drug Discovery for the Oxytocin Receptor.

The oxytocin receptor plays a significant role in peripheral regulation of parturition and lactation. Given this important role, multiple drug discovery programs have been conducted to develop agonists and antagonists for peripheral activity. The role of the oxytocin receptor in the central nervous system is also significant, promoting social interaction, trust, and empathy in humans. As such, molecules that can access the central nervous system and target the oxytocin receptor are of significant interest. Due to the role of the oxytocin receptor in regulating social function and psychological well-being, agonists of this receptor have considerable promise for the treatment of numerous neuropsychiatric conditions. The poor pharmacokinetic properties and blood-brain barrier penetration of peptide-based molecules means nonpeptide compounds have more commonly been the focus for central nervous system activity. This chapter aims to summarize the current standing of peptide and nonpeptide drug discovery for antagonists and agonists of the oxytocin receptor and focusses on centrally active nonpeptidic agonists.

An Overview of Peptide-Based Molecules as Potential Drug Candidates for Multiple Sclerosis.

Multiple sclerosis (MS) belongs to demyelinating diseases, which are progressive and highly debilitating pathologies that imply a high burden both on individual patients and on society. Currently, several treatment strategies differ in the route of administration, adverse events, and possible risks. Side effects associated with multiple sclerosis medications range from mild symptoms, such as flu-like or irritation at the injection site, to serious ones, such as progressive multifocal leukoencephalopathy and other life-threatening events. Moreover, the agents so far available have proved incapable of fully preventing disease progression, mostly during the phases that consist of continuous, accumulating disability. Thus, new treatment strategies, able to halt or even reverse disease progression and specific for targeting solely the pathways that contribute to the disease pathogenesis, are highly desirable. Here, we provide an overview of the recent literature about peptide-based systems tested on experimental autoimmune encephalitis (EAE) models. Since peptides are considered a unique therapeutic niche and important elements in the pharmaceutical landscape, they could open up new therapeutic opportunities for the treatment of MS.

Protein-Peptide Binding Site Detection Using 3D Convolutional Neural Networks.

Peptides and peptide-based molecules represent a promising therapeutic modality targeting intracellular protein-protein interactions, potentially combining the beneficial properties of biologics and small-molecule drugs. Protein-peptide complexes occupy a unique niche of interaction interfaces with respect to protein-protein and protein-small molecule complexes. Protein-peptide binding site identification resembles image object detection, a field that had been revolutionalized with computer vision techniques. We present a new protein-peptide binding site detection method called BiteNetPp by harnessing the power of 3D convolutional neural network. Our method employs a tensor-based representation of spatial protein structures, which is fed to 3D convolutional neural network, resulting in probability scores and coordinates of the binding "hot spots" in the input structures. We used the domain adaptation technique to fine-tune model trained on protein-small molecule complexes using a manually curated set of protein-peptide structures. BiteNetPp consistently outperforms existing state-of-the-art methods in the independent test benchmark. It takes less than a second to analyze a single-protein structure, making BiteNetPp suitable for the large-scale analysis of protein-peptide binding sites.

The Present and Future Role of Microfluidics for Protein and Peptide-Based Therapeutics and Diagnostics

The implementation of peptide-based molecules within the medical field has vast potential, owing to their unique nature and predictable physicochemical profiles. However, peptide therapeutic usage is hindered by delivery-related challenges, meaning that their formulations must be altered to overcome these limitations. This process could be propelled by applying microfluidics (MFs) due to its highly controllable and adaptable attributes; however, therapeutic research within this field is extremely limited. Peptides possess multifunctional roles within therapeutic formulations, ranging from enhancing target specificity to acting as the active component of the medicine. Diagnostically, MFs are well explored in the field of peptides, as MFs provide an unsullied platform to provide fast yet accurate examinations. The capacity to add attributes, such as integrated sensors and microwells, to the MF chip, only enhances the attractiveness of MFs as a diagnostic platform. The structural individuality of peptides makes them prime candidates for diagnostic purposes, for example, antigen detection and isolation. Therefore, this review provides a useful insight into the current applications of MFs for peptide-based therapy and diagnostics and highlights potential gaps in the field that are yet to be explored or optimized.

Microtubule-Targeted Self-Assembly Triggers Prometaphase-Metaphase Oscillations Suppressing Tumor Growth.

Microtubules are highly strategic targets of cancer therapies. Small molecule antimitotic agents are so far the best chemotherapeutic medication in cancer treatment. However, the high rate of neuropathy and drug resistance limit their clinical usage. Inspired by the multicomponent-targeting feature of molecular self-assembly (MSA) overcoming drug resistance, we synthesized peptide-based rotor molecules that self-assemble in response to the surrounding environment to target the microtubule array. The MSAs self-adjust morphologically in response to the pH change and viscosity variations during Golgi-endosome trafficking, escape trafficking cargos, and eventually bind to the microtubule array physically in a nonspecific manner. Such unrefined nano-bio interactions suppress regional tubulin polymerization triggering atypical prometaphase--metaphase oscillations to inhibit various cancer cells proliferating without inducing obvious neurotoxicity. The MSA also exerts potent antiproliferative effects in the subcutaneous cervix cancer xenograft tumor model equivalent to Cisplatin, better than the classic antimitotic drug Taxol.

Peptide Dendrimers with Non-Symmetric Bola Structure Exert Long Term Effect on Glioblastoma and Neuroblastoma Cell Lines.

Background: Glioblastoma (GBM) is the most common malignant tumor of the central nervous system (CNS). Neuroblastoma (NB) is one of the most common cancers of childhood derived from the neural crest cells. The survival rate for patients with GBM and high-risk NB is poor; therefore, novel therapeutic approaches are needed. Increasing evidence suggests a dual role of redox-active compounds in both tumorigenesis and cancer treatment. Therefore, in this study, polyfunctional peptide-based dendrimeric molecules of the bola structure carrying residues with antiproliferative potential on one side and the antioxidant residues on the other side were designed. Methods: We synthesized non-symmetric bola dendrimers and assessed their radical scavenging potency as well as redox capability. The influence of dendrimers on viability of rat primary cerebellar neurons (CGC) and normal human astrocytes (NHA) was determined by propidium iodide staining and cell counting. Cytotoxicity against human GBM cell lines, T98G and LN229, and NB cell line SH-SY5Y was assessed by cell counting and colony forming assay. Results: Testing of CGC and NHA viability allowed to establish a range of optimal dendrimers structure and concentration for further evaluation of their impact on two human GBM and one human NB cell lines. According to ABTS, DPPH, FRAP, and CUPRAC antioxidant tests, the most toxic for normal cells were dendrimers with high charge and an excess of antioxidant residues (Trp and PABA) on both sides of the bola structure. At 5 μM concentration, most of the tested dendrimers neither reduced rat CGC viability below 50–40%, nor harmed human neurons (NHA). The same dose of compounds 16 or 22, after 30 min treatment decreased the number of SH-SY5Y and LN229 cells, but did not affect the number of T98G cells 48 h post treatment. However, either compound significantly reduced the number of colonies formed by SH-SY5Y, LN229, and T98G cells measured 14 days after treatment. Conclusions: Peptide dendrimers with non-symmetric bola structure are excellent scaffolds for design of molecules with pro/antioxidant functionality. Design of molecules with an excess of positive charges and antioxidant residues rendered molecules with high neurotoxicity. Single, 30 min exposition of the GBM and NB cell lines to the selected bola dendrimers significantly suppressed their clonogenic potential