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Explicit solvent model of the biomolecular system consisting of the CTLA4 receptor protein, represented as a gray surface, and a designed peptide, respresented by bonds (H, white; C, green; N, blue; O, red). Na +
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Proteins involved in immune checkpoint pathways, such as CTLA4, PD1, and PD-L1, have become important targets for cancer immunotherapy; however, development of small molecule drugs targeting these pathways has proven difficult due to the nature of their protein-protein interfaces. Here, using a hierarchy of computational techniques, we design a cyc...
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... (N-terminal to C-terminal) peptide bond. The structures of the complexes were solvated using the CHARMM version of the TIP3P 56 water model. Salt ions were added to give Na + and Cl − concentrations of approximately 150 mmol/L. Four additional Na + ions were included to neutralize the system. An exemplary simulation system is shown in Fig. 3. VMD was used to aid structure building, analysis, and visualization. 57 The mass of solute hydrogen atoms was repartitioned to allow a 4 femtosecond timestep to improve computational efficiency. 58 The Lennard-Jones interactions between pair of atoms was calculated using cutoff distance of 12 Å, smoothly truncated beginning at 10 Å. ...
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... 16, the PTG turn common to both peptides has been displaced about 15 Å farther from the MYPPPY loop. Furthermore, the orientation of Peptide 16 is flipped with respect to the template peptide: for example, residue I86 of B7-2 is oriented toward CTLA4, while the corresponding residue in Peptide 16, I2, is oriented toward the solution. As shown in Fig. S3A of the ESI, † the cyclized template peptide with its original coordinates did not remain bound for a long time (< 100 ns) to CTLA4 in the absence of the rest of the B7-2 protein. Hence, it seems that choosing a template from B7-2 provided no benefit and equally good or better results might have been obtained with another template. In ...
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... Moreover, the RDF analysis for the antagonist and the main binding site of in their monomeric forms aligns with the COM results (Supplementary Figure garding TLR1 and TLR2 in all species, the first peak occurs approximately at 0.5 nifying a strong interaction between the antagonist and the main binding site of T TLR2 across all species. Conversely, for TLR6, the initial peak occurs at approxi To provide further clarity on the interaction between the antagonist and the bovine TLRs, we conducted RMSD calculations for both the bound and unbound states of the antagonist and the TLRs [19]. The results are illustrated in Supplementary Figure S7. ...
Toll-like receptor 2 (TLR2) is a major membrane-bound receptor with ligand and species specificity that activates the host immune response. Heterodimerization of TLR2 with TLR1 (TLR2/1) or TLR6 (TLR2/6), triggered by ligand binding, is essential to initiating the signaling pathway. Bovine TLR2 (bTLR2) heterodimerization has not been defined yet compared with human and mouse TLR2s (hTLR2 and mTLR2). The aim of the present study was to model bovine TLRs (TLRs 1, 2 and 6) and create the heterodimeric forms of the bovine TLR2 using molecular dynamics (MD) simulations. We compared the intermolecular interactions in bTLR2/1-PAM3 and bTLR2/6-PAM2 with the hTLR2 and mTLR2 complexes through docking simulations and subsequent MD analyses. The present computational findings showed that bTLR2 dimerization could have a biological function and activate the immune response, similar to hTLR2 and mTLR2. Agonists and antagonists that are designed for hTLR2 and mTLR2 can target bTLR2. However, the experimental approaches to comparing the functional immune response of TLR2 across species were missing in the present study. This computational study provides a structural analysis of the bTLR2 interaction with bTLR1 and bTLR6 in the presence of an agonist/antagonist and reveals the three-dimensional structure of bTLR2 dimerization. The present findings could guide future experimental studies targeting bTLR2 with different ligands and lipopeptides.
... [33][34][35] Notably, numerous studies have demonstrated the efficacy of cyclic peptides in modulating key pathways of multiple immune checkpoints, providing the basis for the high of cyclic peptides as next-generation cancer immunotherapies. [36][37][38] . ...
... Unfortunately, we were not able to provide any additional cues on the molecular details of this interaction model, since neither a crystallographic structure of ABHD2 nor a known P4 antagonist on this receptor are currently available. In this regard, biolayer interferometry analysis will be helpful in support of the computational findings [22]. ...
Abhydrolase domain containing 2-acylglycerol lipase (ABHD2) was recently claimed as the membrane receptor of progesterone (P4) in sperm cells, mediating cell processes such as sperm chemotaxis and acrosome reaction. Here, we investigated the role of membrane cholesterol (Chol) on ABHD2-mediated human sperm chemotaxis. Human sperm cells were obtained from twelve normozoospemic healthy donors. ABHD2–Chol interaction was modelled by computational molecular-modelling (MM). Sperm membrane Chol content was depleted by incubating cells with cyclodextrin (CD) or augmented by the incubation with the complex between CD and Chol (CD:Chol). Cell Chol levels were quantified by liquid chromatography-mass spectrometry. Sperm migration upon P4 gradient was evaluated through the accumulation assay in a specific migration device. Motility parameters were evaluated by sperm class analyzer, whilst intracellular calcium concentration, acrosome reaction and mitochondrial membrane potential were evaluated with calcium orange, FITC-conjugated anti-CD46 antibody and JC-1 fluorescent probes, respectively. MM analysis showed the possible stable binding Chol to ABHD2, resulting in to major impact on the protein backbone flexibility. The treatment with CD was associated with a dose-dependent increase in sperm migration in a 160 nM P4 gradient, together with increase in sperm motility parameters and levels of acrosome reaction. The treatment with CD:Chol was associated with essentially opposite effects. Chol was, thus, suggested to inhibit P4-mediated sperm function through the possible inhibition of ABHD2.
Immunotherapy has emerged as a powerful weapon against lung cancer, yet only a fraction of patients respond to the treatment. Poly(I:C) (PIC) effectively triggers both innate and adaptive immunity. It can also induce immunogenic cell death (ICD) in tumor cells. However, its efficacy is hindered by its instability in vivo and limited cellular uptake. To address this, PIC is encapsulated in cRGD‐functionalized polymersomes (t‐PPIC), which significantly increases its stability and uptake, thus activating dendritic cells (DCs) and inducing apoptosis of lung tumor cells in vitro. In a murine LLC lung tumor model, systemic administration of t‐PPIC effectively suppresses tumor growth and leads to survival benefits, with 40% of the mice becoming tumor‐free. Notably, t‐PPIC provokes stronger apoptosis and ICD in tumor tissue and elicits a more potent stimulation of DCs, recruitment of natural killer (NK) cells, and activation of CD8⁺ T cells, compared to free PIC and nontargeted PPIC controls. Furthermore, when combined with immune checkpoint inhibitors or radiotherapy, t‐PPIC amplifies the antitumor immune response, resulting in complete regression in 60% of the mice. These compelling findings underscore the potential of integrin‐targeted polymersomal PIC to enhance antitumor immunity by simultaneously inducing ICD and systemic immune activation.
Over the last few decades, we have witnessed growing interest from both academic and industrial laboratories in peptides as possible therapeutics. Bioactive peptides have a high potential to treat various diseases with specificity and biological safety. Compared to small molecules, peptides represent better candidates as inhibitors (or general modulators) of key protein–protein interactions. In fact, undruggable proteins containing large and smooth surfaces can be more easily targeted with the conformational plasticity of peptides. The discovery of bioactive peptides, working against disease-relevant protein targets, generally requires the high-throughput screening of large libraries, and in silico approaches are highly exploited for their low-cost incidence and efficiency. The present review reports on the potential challenges linked to the employment of peptides as therapeutics and describes computational approaches, mainly structure-based virtual screening (SBVS), to support the identification of novel peptides for therapeutic implementations. Cutting-edge SBVS strategies are reviewed along with examples of applications focused on diverse classes of bioactive peptides (i.e., anticancer, antimicrobial/antiviral peptides, peptides blocking amyloid fiber formation).
The revolutionary progress in cancer immunotherapy, particularly the advent of immune checkpoint inhibitors, marks a significant milestone in the fight against malignancies. However, the majority of clinically employed immune checkpoint inhibitors are monoclonal antibodies (mAbs) with several limitations, such as poor oral bioavailability and immune-related adverse effects (irAEs). Another major limitation is the restriction of the efficacy of mAbs to a subset of cancer patients, which triggered extensive research efforts to identify alternative approaches in targeting immune checkpoints aiming to overcome the restricted efficacy of mAbs. This comprehensive review aims to explore the cutting-edge developments in targeting immune checkpoints, focusing on both small molecule- and peptide-based approaches. By delving into drug discovery platforms, we provide insights into the diverse strategies employed to identify and optimize small molecules and peptides as inhibitors of immune checkpoints. In addition, we discuss recent advances in nanomaterials as drug carriers, providing a basis for the development of small molecule- and peptide-based platforms for cancer immunotherapy. Ongoing research focused on the discovery of small molecules and peptide-inspired agents targeting immune checkpoints paves the way for developing orally bioavailable agents as the next-generation cancer immunotherapies.
Although effective vaccines have been developed against SARS-CoV-2, many regions in the world still have low rates of vaccination and new variants with mutations in the viral spike protein have reduced the effectiveness of most available vaccines and treatments. There is an urgent need for a drug to cure this disease and prevent infection. The SARS-CoV-2 virus enters the host cell through protein-protein interaction between the virus's spike protein and the host's angiotensin converting enzyme (ACE2). Using protein design software and molecular dynamics simulations, we have designed a 17-residue peptide (pep39), that binds to the spike protein receptor-binding domain (RBD) and blocks interaction of spike protein with ACE2. We have confirmed the binding activity of the designed peptide for the original spike protein and the delta variant spike protein using micro-cantilever and bio-layer interferometry (BLI) based methods. We also confirmed that pep39 strongly inhibits SARS-CoV-2 virus replication in Vero E6 cells. Taken together these data suggest that a newly designed spike protein RBD blocking peptide pep39 has a potential as a SARS-CoV-2 virus inhibitor.
Food-derived bioactive peptides (FBPs) are gaining interest due to their great potential in agricultural byproduct valorization and high-activity peptide screening. The introduction of bioinformatics into FBP studies further enhances the prospects of this field. This review provides a comprehensive overview and critical insight into the latest advances in bioinformatics-driven FBPs studies. The roles of databases, proteolysis simulation, bioactivity potency evaluation, quantitative structure-activity relationships (QSAR) models, molecular docking, molecular dynamics simulation, and free energy calculation in FBP studies are covered. Furthermore, critical issues related to QSAR model development, molecular docking, and integrated bioinformatics strategies are highlighted. By leveraging these bioinformatics approaches, researchers can fully utilize existing knowledge about identified peptides for checking novelty, evaluating bioactivity potency as well as rational peptide and protein hydrolysate design. QSAR models and molecular docking enable efficient screening of thousands of peptide candidates and generate new insights into bioactivity mechanisms. Directions for future research and challenges in current studies are also discussed. The employment of bioinformatics will significantly accelerate the process from the identification of high-potential FBPs to product development, assist in wet chemistry experiment design for targeted protein hydrolysates preparation, and ultimately enhance the long-term development of nutraceutical, pharmaceutical, and cosmeceutical industries.
