The formation of well-ordered nanostructures through self-assembly of diverse organic and inorganic building blocks has drawn much attention owing to their potential applications in biology and ...chemistry. Among all organic building blocks, peptides are one of the most promising platforms due to their biocompatibility, chemical diversity, and resemblance to proteins. Inspired by the protein assembly in biological systems, various self-assembled peptide structures have been constructed using several amino acids and sequences. This review focuses on this emerging area, the recent advances in peptide self-assembly, and formation of different nanostructures, such as tubular structures, fibers, vesicles, and spherical and rod-coil structures. While different peptide nanostructures have been discovered, potential applications are explored in drug delivery, tissue engineering, wound healing, and surfactants.
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.
Nucleoside reverse transcriptase inhibitors (NRTIs) are mainstay therapeutics for HIV that block retrovirus replication. Alu (an endogenous retroelement that also requires reverse transcriptase for ...its life cycle)–derived RNAs activate P2X7 and the NLRP3 inflammasome to cause cell death of the retinal pigment epithelium in geographic atrophy, a type of age-related macular degeneration. We found that NRTIs inhibit P2X7-mediated NLRP3 inflammasome activation independent of reverse transcriptase inhibition. Multiple approved and clinically relevant NRTIs prevented caspase-1 activation, the effector of the NLRP3 inflammasome, induced by Alu RNA. NRTIs were efficacious in mouse models of geographic atrophy, choroidal neovascularization, graft-versus-host disease, and sterile liver inflammation. Our findings suggest that NRTIs are ripe for drug repurposing in P2X7-driven diseases.
Going round in circles: Amphipathic L‐cyclic peptides facilitate the cellular uptake of fluorescently labeled lamivudine and a phosphopeptide. A corresponding fluorescently labeled conjugate F‐W5R4K ...showed a highly efficient translocation in the nucleus of colon adenocarcinoma, breast carcinoma, and human ovarian adenocarcinoma (see picture).
Fungal infections remain a significant concern for human health. The emergence of microbial resistance, the improper use of antimicrobial drugs, and the need for fewer toxic antifungal treatments in ...immunocompromised patients have sparked substantial interest in antifungal research. Cyclic peptides, classified as antifungal peptides, have been in development as potential antifungal agents since 1948. In recent years, there has been growing attention from the scientific community to explore cyclic peptides as a promising strategy for combating antifungal infections caused by pathogenic fungi. The identification of antifungal cyclic peptides from various sources has been possible due to the widespread interest in peptide research in recent decades. It is increasingly important to evaluate narrow- to broad-spectrum antifungal activity and the mode of action of synthetic and natural cyclic peptides for both synthesized and extracted peptides. This short review aims to highlight some of the antifungal cyclic peptides isolated from bacteria, fungi, and plants. This brief review is not intended to present an exhaustive catalog of all known antifungal cyclic peptides but rather seeks to showcase selected cyclic peptides with antifungal properties that have been isolated from bacteria, fungi, plants, and synthetic sources. The addition of commercially available cyclic antifungal peptides serves to corroborate the notion that cyclic peptides can serve as a valuable source for the development of antifungal drugs. Additionally, this review discusses the potential future of utilizing combinations of antifungal peptides from different sources. The review underscores the need for the further exploration of the novel antifungal therapeutic applications of these abundant and diverse cyclic peptides.
Dengue, the oldest and the most prevalent mosquito-borne illness, is caused by the dengue virus (DENV), from the family of Flaviviridae. It infects approximately 400 million individuals per annum, ...with approximately half of the global population residing in high-risk areas. The factors attributed to the geographic expansion of dengue, include urbanization, population density, modern means of transportation, international travels, habit modification, climate change, virus genetics, vector capacity, and poor vector control. Despite the significant progress made in the past against dengue, no effective antiviral therapy is currently available. Among the structural and non-structural proteins encoded by DENV genome, the NS2B-NS3 protease complex is amongst the extensively studied targets for the development of antiviral therapeutics owing to its multiple roles in virus life cycle. Furthermore, protease inhibitors were found to be successful in Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV). Likewise, several peptidic, peptide derived/peptidomimetic, and small molecules inhibitors have been identified as DENV protease inhibitors. Unfortunately, none of them have resulted in a clinically approved drug. Considering all the abovementioned facts, this review descriptively explains the molecular mechanism and therapeutic potential of DENV protease along with an up to date information on various competitive inhibitors reported against DENV protease. This review might be helpful for the researchers working in this area to understand the critical aspects of DENV protease that will help them develop effective and novel inhibitors against DENV to protect lives of millions of people worldwide.
Remdesivir is a nucleotide prodrug that is currently undergoing extensive clinical trials for the treatment of COVID-19. The prodrug is metabolized to its active triphosphate form and interferes with ...the action of RNA-dependent RNA polymerase of SARS-COV-2. Herein, we report the antiviral activity of remdesivir against human coronavirus 229E (HCoV-229E) compared to known anti-HIV agents. These agents included tenofovir (TFV), 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC), known as nucleoside reverse-transcriptase inhibitors (NRTIs), and a number of 5'-
-fatty acylated anti-HIV nucleoside conjugates. The anti-HIV nucleosides interfere with HIV RNA-dependent DNA polymerase and/or act as chain terminators. Normal human fibroblast lung cells (MRC-5) were used to determine the cytotoxicity of the compounds. The study revealed that remdesivir exhibited an EC
value of 0.07 µM against HCoV-229E with TC
of > 2.00 µM against MRC-5 cells. Parent NRTIs were found to be inactive against (HCoV-229E) at tested concentrations. Among all the NRTIs and 5'-
-fatty acyl conjugates of NRTIs, 5'-
-tetradecanoyl ester conjugate of FTC showed modest activity with EC
and TC
values of 72.8 µM and 87.5 µM, respectively. These data can be used for the design of potential compounds against other coronaviruses.
Cell-penetrating peptide WR₅ has been previously shown to be an efficient molecular transporter for various hydrophilic and hydrophobic molecules. The peptide was synthesized using Fmoc/tBu ...solid-phase chemistry, and one arginine was replaced with one lysine to enable the conjugation with the anticancer drugs. Paclitaxel (PTX) was functionalized with an esterification reaction at the C2' hydroxyl group of PTX with glutaric anhydride and conjugated with the cyclic peptide W(WR)₄K(
Ala) in DMF to obtain the peptide-drug conjugate PTX1. Furthermore, camptothecin (CPT) was modified at the C(20)-hydroxyl group through the reaction with triphosgene. Then, it was conjugated with two functionalized cyclic peptides through a formyl linker affording two different conjugates, namely CPT1 and CPT2. All the conjugates showed better water solubility as compared to the parent drug. The cytotoxicity assay of the drugs and their conjugates with the peptides were evaluated in the human breast cancer MCF-7 cell line. PTX inhibited cell proliferation by 39% while the PTX-peptide conjugate inhibited the proliferation by ~18% after 72 h incubation. On the other hand, CPT, CPT1, and CPT2 reduced the cell proliferation by 68%, 39%, and 62%, respectively, in the MCF-7 cell lines at 5 µM concentration after 72 h incubation.
In medicinal chemistry there is a growing interest in using small molecules, including plant stress hormones. Jasmonic acid (JA) and its volatile methyl ester (MJ), collectively termed jasmonates, ...are lipid‐derived cyclopentanone compounds that occur ubiquitously and exclusively in the plant kingdom. This review covers the synthesis, usage, and biological activities of JA and its derivatives. A brief overview of the available information on JA and its features is given, followed by a detailed review of JA and its derivatives as drugs and prodrugs; the properties in plants and the synthesis in recent patents are described. This review shows the direction of long‐term drug/nutraceutical safety trials and provides insights for future research in this area. Research on JA continues to be of major interest. Recent innovations offer hope for the development of new therapeutics in related fields. It is anticipated that several analogs can be advanced to preclinical and clinical studies.
Jasmonic acid and its volatile methyl ester, collectively termed jasmonates, are lipid‐derived cyclopentanone compounds that occur ubiquitously and exclusively in the plant kingdom. The synthesis, usage, and biological activities of jasmonic acid and its derivatives is covered. A few analogs may be advanced to preclinical and clinical studies.
The biological significance of benzopyran-4-ones as cytotoxic agents against multi-drug resistant cancer cell lines and isoxazoles as anti-inflammatory agents in cellular assays prompted us to design ...and synthesize their hybrid compounds and explore their antiproliferative activity against a panel of six cancer cell lines and two normal cell lines. Compounds
-
displayed significant antiproliferative activities against all the cancer cell lines tested, and IC
values were in the range of 5.2-22.2 μM against MDA-MB-231 cancer cells, while they were minimally cytotoxic to the HEK-293 and LLC-PK1 normal cell lines. The IC
values of
-
against normal HEK-293 cells were in the range of 102.4-293.2 μM. Compound
was screened for kinase inhibitory activity, proteolytic human serum stability, and apoptotic activity. The compound was found inactive towards different kinases, while it completely degraded after 2 h of incubation with human serum. At 5 μM concentration, it induced apoptosis in MDA-MB-231 by 50.8%. Overall, these findings suggest that new benzopyran-4-one-isoxazole hybrid compounds, particularly
-
, are selective anticancer agents, potentially safe for human cells, and could be synthesized at low cost. Additionally, Compound
exhibits potential anticancer activity mediated via inhibition of cancer cell proliferation and induction of apoptosis.
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