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 .......
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.
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.
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.
The success of innovative drugs depends on an interdisciplinary and holistic approach to their design and development. The supramolecular architecture of living systems is controlled by non-covalent ...interactions to a very large extent. The latter are prone to extensive cooperation and like a virtuoso play a symphony of life
Thus, the design of effective ligands should be based on thorough knowledge on the interactions at either a molecular or high topological level. In this work, we emphasize the importance of supramolecular structure and ligand-based design keeping the potential of supramolecular H-bonding synthons in focus. In this respect, the relevance of supramolecular chemistry for advanced therapies is appreciated and undisputable. It has developed tools, such as Hirshfeld surface analysis, using a huge data on supramolecular interactions in over one million structures which are deposited in the Cambridge Structure Database (CSD). In particular, molecular interaction surfaces are useful for identification of macromolecular active sites followed by
docking experiments. Ornithine-derived compounds are a new, promising class of multi-targeting ligands for innovative therapeutics and cosmeceuticals. In this work, we present the synthesis together with the molecular and supramolecular structure of a novel ornithine derivative, namely
-α,
-δ)-dibenzoyl-(α)-hydroxymethylornithine,
. It was investigated by modern experimental and
methods in detail. The incorporation of an aromatic system into the ornithine core induces stacking interactions, which are vital in biological processes. In particular, rare C=O
π intercontacts have been identified in
. Supramolecular interactions were analyzed in all structures of ornithine derivatives deposited in the CSD. The influence of substituent was assessed by the Hirshfeld surface analysis. It revealed that the crystal packing is stabilized mainly by H
O, O
H, C
H, Cl (Br, F)
H and O
O interactions. Additionally, π
π, C-H
π and N-O
π interactions were also observed. All relevant H-bond energies were calculated using the Lippincott and Schroeder H-bond model. A library of synthons is provided. In addition, the large synthons (
) were considered. The DFT optimization either
or
yields very similar molecular species. The major difference with the relevant crystal structure was related to the conformation of terminal benzoyl C15-C20 ring. Furthermore,
prediction of the extensive physicochemical ADME profile (absorption, distribution, metabolism and excretion) related to the drug-likeness and medicinal chemistry friendliness revealed that a novel ornithine derivative
has the potential to be a new drug candidate. It has shown good
absorption and very low toxicity.
A series of novel salts of heterocyclic polyamines with 5-sulfosalicylic acid (C4H7N4+)(C7H5O6S−)∙2(H2O) (1), (C4H6ClN4+)(C7H5O6S−)∙H2O (2), (C5H8N3+)(C7H5O6S−)∙H2O (3), (C5H7N6+)(C7H5O6S−)∙H2O (4), ...(C6H14N22+)(C7H4O6S2−)∙H2O (5), and (C14H19N2+)(C7H5O6S−) (6) have been successfully synthesized. Their crystal structures have been determined by single-crystal X-ray diffraction. Overall, compounds adopt a layered structure with aminium cations and 5-sulfosalicylic anions linked via water molecules. The solid-state architectures of these compounds are dominated by O(N,H)-H⋯O and N-H⋯N hydrogen bonds and stabilized by weak interconnects. C-Cl⋯π and S-O⋯π interactions, apart from π⋯π and C-H(O)⋯π, were reported. Diverse approaches were used to study the effect of substituents in the polyamines in solid-state arrangement. A Hirshfeld surface analysis, with associated 3D Hirshfeld surface maps and 2D fingerprint plots, molecular electrostatic potential, and energy frameworks were used to comprehensively investigate the nature and hierarchy of non-covalent interactions and inspect supramolecular differences. The contact enrichment ratio calculations provided deeper insight into the propensity of interconnects to influence crystal packing. The evaluation of the effects of H-bonding synthons resulting from different substituents in the polyamines on self-assemblies is also presented. In the context of crystal engineering, a specific intramolecular synthon via O-H⋯O observed in nearly all crystals can be employed in the pseudo-cyclic replacement strategy in the design of new molecules.
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.
The crystal structures and the supramolecular architectures of a series of novel salts originating from 2,4-diaminopyrimidine and four different chain dicarboxylic acids are reported. For this ...purpose, 2,4-diaminopyrimidin-1-ium 2,2′-thio(acetic)acetate (1), 2,4-diaminopyrimidin-1-ium monoglutarate (2), 2,4-diaminopyrimidin-1-ium 3,3′-dithio(propionic)propionate (3) and 2,4-diaminopyrimidin-1-ium suberate (4) were synthesized in good to high yields from 2,4-diaminopyrimidine and appropriate dicarboxylic acids (2,2′-thiodiacetic acid, glutaric acid, 3,3′-dithiodipropionic acid and suberic acid, respectively). Each of the compounds were formed as a monohydrate and compound 4 additionally co-crystallized with the suberic acid molecule. Despite the similar structures of compounds 1 and 2 as well as 3 and 4, subtle but important differences are observed in their crystal packing and H-bonding patterns, especially between 3 and 4. Supramolecular self-assemblies can be distinguished through different interactions considering anions, leading to diverse H-bonding motifs, which also include sulphur atoms in 1 and 3, at the upper level of supramolecular architecture. Notably, the basic motif is always the same—2,4-diaminopyrimidine-based homosynthon R22(8) via N-H∙∙∙N interactions. The impact of diverse types of intermolecular interactions was evaluated by Hirshfeld analysis, while the propensity of atom pairs of elements to build interactions was calculated using enrichment ratios. Although compounds 1 and 3 contain S-atoms, the percentage of S-derived interactions is rather low. In 1, the contribution of S∙∙∙H/H∙∙∙S, S∙∙∙C/C∙∙∙S, S∙∙∙N/N∙∙∙S intermolecular contacts is 5.7%. In 2, the contribution of S∙∙∙H/H∙∙∙S accounts for only 0.6%.
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.
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