An experimental and computational investigation of the cyclopentene-containing peptide-derived compounds: focus on pseudo-cyclic motifs via intramolecular interactions.

Conformational flexibility is one of the main disadvantages of peptide-based compounds. We focus on their molecular 'chameleonicity' related to forming pseudo-cyclic motifs via modulation of weak intramolecular interactions. It is an appealing strategy for controlling equilibrium between the polar open and the nonpolar closed conformations. Within this context, we report here the crystal structure of the (R)-(2-tert-butoxycarbonyl)amino-1-oxo-3-phenyl)propyl)-1-cyclopentene (1), synthesis of which in high yield was achieved by a facile multi-step protocol. Our Cambridge Structural Database (CSD) overview for the peptide-based crystals revealed the exclusivity of this compound from the viewpoint of the unusual pseudo-bicyclic system via C-H…O and C-O…π interactions, in which cyclopentene shields the amide bond. Notably, cyclopentene as a bioisostere of proline is an appealing scaffold in medicinal chemistry. An extensive combined experimental and computational study provided more profound insight into the supramolecular landscape of 1 with respect to similar derivatives deposited in the CSD, including the tendency of cyclopentene for the generation of pseudo-cyclic motifs through weak H-bonding and π-based intramolecular interactions. These weak interactions have been examined by either the quantum theory of 'atoms-in-molecules' (QTAIM) or complex Hirshfeld surface methodology, including enrichment ratios, molecular electrostatic potential surfaces and energy frameworks. In all analysed crystals, all types of H-bonded motifs involving cyclopentene are formed at all levels of supramolecular architecture. A library of cyclopentene-based H-bonding synthons is provided. A molecular docking study depicted vital interactions of cyclopentene with key amino acid residues inside the active sites of two prominent protein kinases, uncovering the therapeutic potential of 1 against breast cancer. To a large extent, dispersion forces have significance in stabilizing the supramolecular structure of both ligand and bio-complex ligand-protein. Finally, the satisfactory in silico bio-pharmacokinetic profile of 1 related to drug-likeness and blood-brain barrier permeation was also revealed.

Short Peptides as Powerful Arsenal for Smart Fighting Cancer.

Short peptides have been coming around as a strong weapon in the fight against cancer on all fronts-in immuno-, chemo-, and radiotherapy, and also in combinatorial approaches. Moreover, short peptides have relevance in cancer imaging or 3D culture. Thanks to the natural 'smart' nature of short peptides, their unique structural features, as well as recent progress in biotechnological and bioinformatics development, short peptides are playing an enormous role in evolving cutting-edge strategies. Self-assembling short peptides may create excellent structures to stimulate cytotoxic immune responses, which is essential for cancer immunotherapy. Short peptides can help establish versatile strategies with high biosafety and effectiveness. Supramolecular short peptide-based cancer vaccines entered clinical trials. Peptide assemblies can be platforms for the delivery of antigens, adjuvants, immune cells, and/or drugs. Short peptides have been unappreciated, especially in the vaccine aspect. Meanwhile, they still hide the undiscovered unlimited potential. Here, we provide a timely update on this highly active and fast-evolving field.

Tetrazoles: A multi-potent motif in drug design.

The unique physicochemical properties and fascinating bioisosterism of tetrazole scaffolds have received significant attention in medicinal chemistry. We report recent efforts using tetrazoles in drug design strategies in this context. Despite the increasing prevalence of tetrazoles in FDA-approved drugs for various conditions such as cancer, bacterial viral and fungal infections, asthma, hypertension, Alzheimer's disease, malaria, and tuberculosis, our understanding of their structure-activity relationships, multifunctional mechanisms, binding modes, and biochemical properties remains limited. We explore the potential of tetrazole bioisosteres in optimising lead molecules for innovative therapies, discussing applications, trends, advantages, limitations, and challenges. Additionally, we assess future research directions to drive further progress in this field.

The Immunosuppressive Properties of Cyclo-[D-Pro-Pro-ß3-HoPhe-Phe-] Tetrapeptide Selected from Stereochemical Variants of Cyclo-[Pro-Pro-ß3-HoPhe-Phe-] Peptide.

The anti-inflammatory, antiviral, and anti-cancer properties, as well as the mechanism of action of cyclo-[Pro-Pro-ß3-HoPhe-Phe-] tetrapeptide (denoted as 4B8M), were recently described. The aim of this work was to synthesize and evaluate the immunosuppressive actions of the stereochemical variants of 4B8M by sequential substitution of L-amino acids by D-amino acids (a series of peptides denoted as P01-P07) using parent 4B8M as a reference compound. In addition, diverse available bioinformatics tools using machine learning and artificial intelligence were tested to find the bio-pharmacokinetic and polypharmacological attributes of analyzed stereomers. All peptides were non-toxic to human peripheral blood mononuclear cells (PBMCs) and only cyclo-[D-Pro-Pro-ß3-HoPhe-Phe-] peptide (P03) was capable of inhibiting mitogen-induced PBMC proliferation. The peptides inhibited the lipopolysaccharide (LPS)-induced production of tumor necrosis factor-alpha (TNF-α) to various degrees, with P04 (cyclo-[Pro-Pro-D-ß3-HoPhe-Phe-]) and P03 being the most potent. For further in vivo studies, P03 was selected because it had the combined properties of inhibiting cell proliferation and TNF-α production. P03 demonstrated a comparable ability to 4B8M in the inhibition of auricle edema and lymph node cell number and in the normalization of a distorted blood cell composition in contact sensitivity to the oxazolone mouse model. In the mouse model of carrageenan-induced inflammation of the air pouch, P03 exhibited a similar inhibition of the cell number in the air pouches as 4B8M, but its inhibitory effects on the percentage of neutrophils and eosinophils in the air pouches and blood, as well as on mastocyte degranulation in the air pouches, were stronger in comparison to 4B8M. Lastly, in a mouse model of dextran sulfate-induced colitis, similar effects to 4B8M regarding thymocyte number restoration and normalization of the blood cell pictures by P03 were observed. In summary, depending on either experimental findings or in silico predictions, P03 demonstrated comparable, or even better, anti-inflammatory and bio-pharmacokinetic properties to 4B8M and may be considered as a potential therapeutic. The possibility of P00 and P03 identification by circular dichroism measurements was tested by quantum-chemical calculations.

Self-assembled peptide hydrogels for the treatment of diabetes and associated complications.

Diabetes is a widespread epidemic that includes a number of comorbid conditions that greatly increase the chance of acquiring other chronic illnesses. Every year, there are significantly more people with diabetes because of the rise in type-2 diabetes prevalence. The primary causes of illness and mortality worldwide are, among these, hyperglycemia and its comorbidities. There has been a lot of interest in the creation of peptide-based hydrogels as a potentially effective platform for the treatment of diabetes and its consequences. Here, we emphasize the use of self-assembled hydrogel formulations and their unique potential for the treatment/management of type-2 diabetes and its consequences. (i.e., wounds). Key aspects covered include the characteristics of self-assembled peptide hydrogels, methods for their preparation, and their pre-clinical and clinical applications in addressing metabolic disorders such as type-2 diabetes.

Antimicrobial Photodynamic Therapy against Escherichia coli and Staphylococcus aureus Using Nanoemulsion-Encapsulated Zinc Phthalocyanine.

Multidrug-resistant microorganisms have become a significant public health threat, and traditional antibiotics are becoming ineffective. Photodynamic therapy (PDT) is a promising alternative that utilizes photosensitizers and light to produce Reactive Oxygen Species (ROS) that can kill microorganisms. Zinc phthalocyanine (ZnPc) is a promising photosensitizer due to its strong affinity for encapsulation in nanoemulsions and its antimicrobial properties. In this study, nanoemulsion was prepared using Miglyol 812N, a surfactant, and distilled water to dissolve hydrophobic drugs such as ZnPc. The nanoemulsion was characterized by its particle size, polydispersity index, Transmission Electron Microscope and Zeta potential, and the results showed that it was an efficient nanocarrier system that facilitated the solubilization of hydrophobic drugs in water. The use of ZnPc encapsulated in the nanoemulsion produced through the spontaneous emulsification method resulted in a significant reduction in cell survival percentages of gram-positive Staphylococcus aureus and gram-negative Escherichia coli by 85% and 75%, respectively. This may be attributed to the more complex cell membrane structure of E. coli compared to S. aureus. This demonstrates the potential of nanoemulsion-based PDT as an effective alternative to traditional antibiotics for treating multidrug-resistant microorganisms.

Antibody-Biopolymer Conjugates in Oncology: A Review.

Cancer is one of the most prevalent diseases and affects a large proportion of the population worldwide. Conventional treatments in the management include chemotherapy, radiotherapy, and surgery. Although being well-accepted, they have many lacunas in the form of severe side effect resulting from lack of targeted delivery. Antibody biopolymer conjugates are a novel method which is an add-on to older methods of immunization. It is used in various diseases and disorders. It ensures the targeted delivery of molecules to increase its efficacy and reduce unwanted effects of the molecule/drug to normal cells. It shows miraculous results in the treatment and management of several cancers even in advanced stages. Herein, we present the chemistry between biopolymer and antibody, their effects on cancer as well as the basic differences between antibody-drug conjugates and antibody-biopolymer conjugates.

Bioactive Peptide Discovery from Edible Insects for Potential Applications in Human Health and Agriculture.

In the past decade, there has been fast-growing interest among researchers to discover bioactive peptides from edible insects and to evaluate their potential applications in the management of human, livestock, and plant health. This review summarizes current knowledge of insect-derived peptides and their potential role in tackling human health issues and solving agriculture problems by protecting crops and livestock against their pathogens. Numerous bioactive peptides have been identified from edible insect species, including peptides that were enzymatically liberated from insect proteins and endogenous peptides that occur naturally in insects. The peptides exhibited diverse bioactivities, encompassing antioxidant, anti-angiotensin-converting enzyme, anti-dipeptidyl peptidase-IV, anti-glucosidase, anti-lipase, anti-lipoxygenase, anti-cyclooxygenase, anti-obesity, and hepatoprotective activities. Such findings point to their potential contribution to solving human health problems related to inflammation, free radical damage, diabetes, hypertension, and liver damage, among others. Although most of the experiments were performed in vitro, evidence for the in vivo efficacy of some peptides is emerging. Evidence of the protective effects of insect-derived endogenous antimicrobial peptides in combating farm animal and plant pathogens is available. The ability of insect-derived endogenous neuropeptides to protect plants against herbivorous insects has been demonstrated as well. Nevertheless, the potency of peptides identified from insect protein hydrolysates in modulating livestock and plant health remains a knowledge gap to be filled.

Peptide-Drug Conjugates: A New Hope for Cancer Management.

Cancer remains the leading cause of death worldwide despite advances in treatment options for patients. As such, safe and effective therapeutics are required. Short peptides provide advantages to be used in cancer management due to their unique properties, amazing versatility, and progress in biotechnology to overcome peptide limitations. Several appealing peptide-based therapeutic strategies have been developed. Here, we provide an overview of peptide conjugates, the better equivalents of antibody-drug conjugates, as the next generation of drugs for required precise targeting, enhanced cellular permeability, improved drug selectivity, and reduced toxicity for the efficient treatment of cancers. We discuss the basic components of drug conjugates and their release action, including the release of cytotoxins from the linker. We also present peptide-drug conjugates under different stages of clinical development as well as regulatory and other challenges.

Actions of Novel Angiotensin Receptor Blocking Drugs, Bisartans, Relevant for COVID-19 Therapy: Biased Agonism at Angiotensin Receptors and the Beneficial Effects of Neprilysin in the Renin Angiotensin System.

Angiotensin receptor blockers (ARBs) used in the treatment of hypertension and potentially in SARS-CoV-2 infection exhibit inverse agonist effects at angiotensin AR1 receptors, suggesting the receptor may have evolved to accommodate naturally occurring angiotensin 'antipeptides'. Screening of the human genome has identified a peptide (EGVYVHPV) encoded by mRNA, complementary to that encoding ANG II itself, which is an inverse agonist. Thus, opposite strands of DNA encode peptides with opposite effects at AR1 receptors. Agonism and inverse agonism at AR1 receptors can be explained by a receptor 'switching' between an activated state invoking receptor dimerization/G protein coupling and an inverse agonist state mediated by an alternative/second messenger that is slow to reverse. Both receptor states appear to be driven by the formation of the ANG II charge-relay system involving TyrOH-His/imidazole-Carboxylate (analogous to serine proteases). In this system, tyrosinate species formed are essential for activating AT1 and AT2 receptors. ANGII is also known to bind to the zinc-coordinated metalloprotease angiotensin converting enzyme 2 (ACE2) used by the COVID-19 virus to enter cells. Here we report in silico results demonstrating the binding of a new class of anionic biphenyl-tetrazole sartans ('Bisartans') to the active site zinc atom of the endopeptidase Neprilysin (NEP) involved in regulating hypertension, by modulating humoral levels of beneficial vasoactive peptides in the RAS such as vasodilator angiotensin (1-7). In vivo and modeling evidence further suggest Bisartans can inhibit ANG II-induced pulmonary edema and may be useful in combatting SARS-CoV-2 infection by inhibiting ACE2-mediated viral entry to cells.

Tirzepatide, a New Era of Dual-Targeted Treatment for Diabetes and Obesity: A Mini-Review.

The prevalence of obesity and diabetes is an increasing global problem, especially in developed countries, and is referred to as the twin epidemics. As such, advanced treatment approaches are needed. Tirzepatide, known as a 'twincretin', is a 'first-in-class' and the only dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptor agonist, that can significantly reduce glycemic levels and improve insulin sensitivity, as well as reducing body weight by more than 20% and improving lipid metabolism. This novel anti-diabetic drug is a synthetic peptide analog of the human GIP hormone with a C20 fatty-diacid portion attached which, via acylation technology, can bind to albumin in order to provide a dose of the drug, by means of subcutaneous injection, once a week, which is appropriate to its a half-life of about five days. Tirzepatide, developed by Eli Lilly, was approved, under the brand name Mounjaro, by the United States Food and Drug Administration in May 2022. This started the 'twincretin' era of enormously important and appealing dual therapeutic options for diabetes and obesity, as well as advanced management of closely related cardiometabolic settings, which constitute the leading cause of morbidity, disability, and mortality worldwide. Herein, we present the key characteristics of tirzepatide in terms of synthesis, structure, and activity, bearing in mind its advantages and shortcomings. Furthermore, we briefly trace the evolution of this kind of medical agent and discuss the development of clinical studies.

Structural and Biofunctional Insights into the Cyclo(Pro-Pro-Phe-Phe-) Scaffold from Experimental and In Silico Studies: Melanoma and Beyond.

Short peptides have great potential as safe and effective anticancer drug leads. Herein, the influence of short cyclic peptides containing the Pro-Pro-Phe-Phe sequence on patient-derived melanoma cells was investigated. Cyclic peptides such as cyclo(Leu-Ile-Ile-Leu-Val-Pro-Pro-Phe-Phe-), called CLA, and cyclo(Pro-homoPro-ß3homoPhe-Phe-), called P11, exert the cytotoxic and the cytostatic effects in melanoma cells, respectively. CLA was the most active peptide as it reduced the viability of melanoma cells to 50% of control at about 10 µM, whereas P11 at about 40 µM after 48 h incubation. Interestingly, a linear derivative of P11 did not induce any effect in melanoma cells confirming previous studies showing that cyclic peptides exert better biological activity compared to their linear counterparts. According to in silico predictions, cyclic tetrapeptides show a better pharmacokinetic and toxic profile to humans than CLA. Notably, the spatial structure of those peptides containing synthetic amino acids has not been explored yet. In the Cambridge Structural Database, there is only one such cyclic tetrapeptide, cyclo((R)-ß2homoPhe-D-Pro-Lys-Phe-), while in the Protein Data Bank-none. Therefore, we report the first crystal structure of cyclo(Pro-Pro-ß3homoPhe-Phe-), denoted as 4B8M, a close analog of P11, which is crucial for drug discovery. Comparative molecular and supramolecular analysis of both structures was performed. The DFT findings revealed that 4B8M is well interpreted in the water solution. The results of complex Hirshfeld surface investigations on the cooperativity of interatomic contacts in terms of electrostatic and energetic features are provided. In short, the enrichment ratio revealed O…H/H…O and C…H/H…C as privileged intercontacts in the crystals in relation to basic and large supramolecular H-bonding synthon patterns. Furthermore, the ability of self-assemble 4B8M leading to a nanotubular structure is also discussed.

New Advances in Short Peptides: Looking Forward.

It is beyond doubt that short peptides hold significant promise in bio-medicine, as the most versatile molecules, both structurally and functionally [...].

Advances in Research of Short Peptides.

Short peptides are unique biomolecules, which combine the advantages of classical small molecules and mature proteins and have attracted increasing interest due to their wide range of applications [...].

Cyclic Dipeptides: The Biological and Structural Landscape with Special Focus on the Anti-Cancer Proline-Based Scaffold.

Cyclic dipeptides, also know as diketopiperazines (DKP), the simplest cyclic forms of peptides widespread in nature, are unsurpassed in their structural and bio-functional diversity. DKPs, especially those containing proline, due to their unique features such as, inter alia, extra-rigid conformation, high resistance to enzyme degradation, increased cell permeability, and expandable ability to bind a diverse of targets with better affinity, have emerged in the last years as biologically pre-validated platforms for the drug discovery. Recent advances have revealed their enormous potential in the development of next-generation theranostics, smart delivery systems, and biomaterials. Here, we present an updated review on the biological and structural profile of these appealing biomolecules, with a particular emphasis on those with anticancer properties, since cancers are the main cause of death all over the world. Additionally, we provide a consideration on supramolecular structuring and synthons, based on the proline-based DKP privileged scaffold, for inspiration in the design of compound libraries in search of ideal ligands, innovative self-assembled nanomaterials, and bio-functional architectures.

The First Insight Into the Supramolecular System of D,L-α-Difluoromethylornithine: A New Antiviral Perspective.

Targeting the polyamine biosynthetic pathway by inhibiting ornithine decarboxylase (ODC) is a powerful approach in the fight against diverse viruses, including SARS-CoV-2. Difluoromethylornithine (DFMO, eflornithine) is the best-known inhibitor of ODC and a broad-spectrum, unique therapeutical agent. Nevertheless, its pharmacokinetic profile is not perfect, especially when large doses are required in antiviral treatment. This article presents a holistic study focusing on the molecular and supramolecular structure of DFMO and the design of its analogues toward the development of safer and more effective formulations. In this context, we provide the first deep insight into the supramolecular system of DFMO supplemented by a comprehensive, qualitative and quantitative survey of non-covalent interactions via Hirshfeld surface, molecular electrostatic potential, enrichment ratio and energy frameworks analysis visualizing 3-D topology of interactions in order to understand the differences in the cooperativity of interactions involved in the formation of either basic or large synthons (Long-range Synthon Aufbau Modules, LSAM) at the subsequent levels of well-organized supramolecular self-assembly, in comparison with the ornithine structure. In the light of the drug discovery, supramolecular studies of amino acids, essential constituents of proteins, are of prime importance. In brief, the same amino-carboxy synthons are observed in the bio-system containing DFMO. DFT calculations revealed that the biological environment changes the molecular structure of DFMO only slightly. The ADMET profile of structural modifications of DFMO and optimization of its analogue as a new promising drug via molecular docking are discussed in detail.

A Global Review on Short Peptides: Frontiers and Perspectives.

Peptides are fragments of proteins that carry out biological functions. They act as signaling entities via all domains of life and interfere with protein-protein interactions, which are indispensable in bio-processes. Short peptides include fundamental molecular information for a prelude to the symphony of life. They have aroused considerable interest due to their unique features and great promise in innovative bio-therapies. This work focusing on the current state-of-the-art short peptide-based therapeutical developments is the first global review written by researchers from all continents, as a celebration of 100 years of peptide therapeutics since the commencement of insulin therapy in the 1920s. Peptide "drugs" initially played only the role of hormone analogs to balance disorders. Nowadays, they achieve numerous biomedical tasks, can cross membranes, or reach intracellular targets. The role of peptides in bio-processes can hardly be mimicked by other chemical substances. The article is divided into independent sections, which are related to either the progress in short peptide-based theranostics or the problems posing challenge to bio-medicine. In particular, the SWOT analysis of short peptides, their relevance in therapies of diverse diseases, improvements in (bio)synthesis platforms, advanced nano-supramolecular technologies, aptamers, altered peptide ligands and in silico methodologies to overcome peptide limitations, modern smart bio-functional materials, vaccines, and drug/gene-targeted delivery systems are discussed.

A Proline-Based Tectons and Supramolecular Synthons for Drug Design 2.0: A Case Study of ACEI.

Proline is a unique, endogenous amino acid, prevalent in proteins and essential for living organisms. It is appreciated as a tecton for the rational design of new bio-active substances. Herein, we present a short overview of the subject. We analyzed 2366 proline-derived structures deposited in the Cambridge Structure Database, with emphasis on the angiotensin-converting enzyme inhibitors. The latter are the first-line antihypertensive and cardiological drugs. Their side effects prompt a search for improved pharmaceuticals. Characterization of tectons (molecular building blocks) and the resulting supramolecular synthons (patterns of intermolecular interactions) involving proline derivatives, as presented in this study, may be useful for in silico molecular docking and macromolecular modeling studies. The DFT, Hirshfeld surface and energy framework methods gave considerable insight into the nature of close inter-contacts and supramolecular topology. Substituents of proline entity are important for the formation and cooperation of synthons. Tectonic subunits contain proline moieties characterized by diverse ionization states: -N and -COOH(-COO-), -N+ and -COOH(-COO-), -NH and -COOH(-COO-), -NH+ and -COOH(-COO-), and -NH2+ and -COOH(-COO-). Furthermore, pharmacological profiles of ACE inhibitors and their impurities were determined via an in silico approach. The above data were used to develop comprehensive classification, which may be useful in further drug design studies.