Bioactive Research Articles

Nonclinical Similarity of the Biosimilar Candidate ABP 938 with Aflibercept Reference Product.

ABP 938 is being developed as a biosimilar to Eylea® (aflibercept reference product [RP]), an anti-vascular endothelial growth factor (VEGF) drug used in the management of retinal diseases. Previously, a comparative analytical similarity assessment demonstrated that ABP 938 and aflibercept RP have the same amino acid sequence and exhibit similar higher-order structure and biological activity. The nonclinical studies described here were designed to assess the in vitro pharmacology and the in vivo pharmacokinetics (PK), toxicokinetics (TK), and safety profiles of ABP 938 compared to aflibercept RP. In vitro target-binding kinetics and affinity for VEGF-A and placental growth factor (PIGF) isoforms were evaluated using surface plasmon resonance (SPR). Effector functions were assessed by cell-based assays. PK was evaluated in a nonterminal intravitreal (IVT) ocular distribution study in rabbits. Safety was assessed in a 1-month IVT study in cynomolgus monkeys. SPR results demonstrated that ABP 938 is similar to aflibercept RP in binding kinetics and affinity for VEGF-A111, VEGF-A121, VEGF-A165, VEGF-A189, PlGF-1, and PlGF-2 isoforms. No antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, or complement-dependent cytotoxicity was observed with ABP 938 and aflibercept RP. Results from thenonterminal ocular distribution study in rabbits indicated that there were no meaningful differences in the distribution kinetics between intravitreally injected ABP 938 and aflibercept RP. Additionally, there was no evidence of ocular or systemic toxicity associated with IVT administration of ABP 938 in a repeat-dose, 1-month toxicology study in cynomolgus monkeys; toxicokinetic and toxicology profiles were similar to aflibercept RP. This integrated assessment of results from the in vitro pharmacology assessment and in vivo PK and TK/toxicology profiles formed the nonclinical portion of the totality of evidence demonstrating ABP938 is a biosimilar to aflibercept RP.

Latin American Natural Product Database (LANaPDB): An Update.

Natural product (NP) databases are crucial tools in computer-aided drug design (CADD). Over the past decade, there has been a worldwide effort to assemble information regarding natural products (NPs) isolated and characterized in certain geographical regions. In 2023, it was published LANaPDB, and to our knowledge, this is the first attempt to gather and standardize all the NP databases of Latin America. Herein, we present and analyze in detail the contents of an updated version of LANaPDB, which includes 619 newly added compounds from Colombia, Costa Rica, and Mexico. The present version of LANaPDB has a total of 13 578 compounds, coming from ten databases of seven Latin American countries. A chemoinformatic characterization of LANaPDB was carried out, which includes the structural classification of the compounds, calculation of six physicochemical properties of pharmaceutical interest, and visualization of the chemical space by employing and comparing two different fingerprints (MACCS keys (166-bit) and Morgan2 (2048-bit)). Furthermore, additional analyses were made, and valuable information not included in the first version of LANaPDB was added, which includes structural diversity, molecular complexity, synthetic feasibility, commercial availability, and reported and predicted biological activity. In addition, the LANaPDB compounds were cross-referenced to two of the largest public chemical compound databases annotated with biological activity: ChEMBL and PubChem.

StaPep: An Open-Source Toolkit for Structure Prediction, Feature Extraction, and Rational Design of Hydrocarbon-Stapled Peptides.

All-hydrocarbon stapled peptides, with their covalent side-chain constraints, provide enhanced proteolytic stability and membrane permeability, making them superior to linear peptides. However, tools for extracting structural and physicochemical descriptors to predict the properties of hydrocarbon-stapled peptides are lacking. To address this, we present StaPep, a Python-based toolkit for generating 3D structures and calculating 21 features for hydrocarbon-stapled peptides. StaPep supports peptides containing two non-standard amino acids (norleucine and 2-aminoisobutyric acid) and six non-natural anchoring residues (S3, S5, S8, R3, R5, and R8), with customization options for other non-standard amino acids. We showcase StaPep's utility through three case studies. The first generates 3D structures of these peptides with a mean RMSD of 1.62 ± 0.86, offering essential structural insights for drug design and biological activity prediction. The second develops machine learning models based on calculated molecular features to differentiate between membrane-permeable and non-permeable stapled peptides, achieving an AUC of 0.93. The third constructs regression models to predict the antimicrobial activity of stapled peptides against Escherichia coli, with a Pearson correlation of 0.84. StaPep's pipeline spans data retrieval, structure generation, feature calculation, and machine learning modeling for hydrocarbon-stapled peptides. The source codes and data set are freely available on Github: https://github.com/dahuilangda/stapep_package.

Cascade [3 + 2]/[4 + 2] Cycloaddition of Enaminones with Vinylene Carbonate for the Synthesis of Functionalized Pyrrolo[2,1-a]isoquinoline Derivatives.

We developed a protocol for the synthesis of functionalized pyrrolo[2,1-a]isoquinoline derivatives (PIQDs) 3 from enaminones 1 using vinylene carbonate 2. This strategy involved [3 + 2] and [4 + 2] cycloadditions via heating a mixture of substrates 1 with vinylene carbonate 2 and DCE at 60 °C, catalyzed by [Cp*RhCl2]2 and oxidized with Cu(OAc)2 and AgSbF6 promoted by NaOAc. As we increased the reaction temperature to 110 °C under the same conditions, we synthesized PIQDs 4 through sequential C-H activation, alkene insertion, migratory insertion, C-N reductive elimination, β-O elimination, and finally dehydration. As a result, a series of PIQDs 3-4 were generated by forming four bonds (2 C-C and 2 C-N bonds) in a single step. This strategy realizes the synthesis of linear molecules with potential biological activity, specifically natural-like heterocycles (3-4). It expands the application of vinylene carbonate as a C2 synthon in the construction of pyrrole and isoquinoline skeletons for the synthesis of functionalized PIQDs in combinatorial and parallel syntheses via one-pot reactions.

Diastereomers of the Anticancer Peptide CIGB-300 with Altered β-Turn Structures

Abstract Purpose The next-generation anti-tumor drug peptide CIGB-300, developed by the Center for Genetic Engineering and Biotechnology (CIGB), targets casein kinase 2 (CK2) and its substrates, implicating significant therapeutic potential in cancer treatment. A key focus of this study was to compare CIGB-300 and a primary synthetic byproduct, CIGB-300iso, which shares the amino acid sequence with CIGB-300 but was proposed to differ due to racemization. Methods This study explores the synthesis, characterization, and structural elucidation of CIGB-300 and its isomer CIGB-300iso by a comprehensive NMR analysis of seven synthesized diastereomers including amino acid residues C15, H21, and C25. Results This study revealed that CIGB-300iso contains one D enantiomer at position H21. The structures of both isoforms derived from NMR constraints disclosed that the L and D enantiomers have an altered peptide supersecondary structure, with a β-turn type IV3 found in CIGB-300 and a type I β-turn in CIGB-300iso. Conclusion The configuration of H21 significantly impacts the peptide’s conformations, sidechain orientations and, potentially, its biological activity. These findings highlight the importance of enantiomerically pure peptides for the design and synthesis of drug peptides.

Diversity of biological activities of crude venom extracted from five species of South China Sea anemones

Developing novel, efficient, and safe peptide drugs from sea anemones has aroused great interest in countries around the world today. Sea anemones contain complex protein and peptide toxins, which determine the diversity of their biological activities. In this study, a variety of activities were assessed for crude venom extracted from five species of South China Sea anemones, including hemolytic, enzyme inhibition, anticancer, insecticidal, analgesic and lethal activities. The most toxic sea anemone was found to be Heteractis magnifica, which has high lethal activity in mice with an LD50 of 11.0 mg/kg. The crude venom of H. magnifica also exhibited a range of the most potent activities, including hemolytic, trypsin inhibitory, cytotoxic activity against U251 and A549 cells, insecticidal and analgesic activities. In addition, the crude venom of Stichodactyla haddoni was the most effective inhibitor of pepsin, and the crude venom of Heteractis crispa was extremely strong toxicity to HepG2 cells. These findings are of great significance for exploring the potential and application of South China Sea anemone resources, and are expected to provide new directions and possibilities for the development of novel anticancer drugs, analgesics and biopesticides.

Valorization of Fish Processing by-Products: Biological and Functional Properties of Bioactive Peptides

Abstract Purpose of Review This review explores the potential of fish by-products as a source of bioactive peptides for the food, pharmaceutical, and cosmetic industries. Focusing on their diverse bioactive and functional properties, it offers insights into their industrial utilization, contributing to a better understanding of their applications. Recent Findings Fish processing by-products, including wastewater and solid residues, serve as valuable sources of bioactive peptides exhibiting a remarkable range of biological activities, such as antioxidant, antimicrobial, and antihypertensive properties. These peptides exhibit a wide range of functional properties, such as solubility, water holding, fat binding, foaming, and emulsifying capacities. Moreover, they show significant potential for various industrial applications. Summary Bioactive peptides derived from fish by-products are attracting interest in multiple industries due to their diverse biological activities and functional properties. These peptides have emerged as a valuable and largely untapped resource, as they can be extracted from underutilized, or waste materials generated during fish processing operations. Graphical Abstract

Exploring the Extraction and Application of Anthocyanins in Food Systems

The continued use of synthetic additives in food production and preservation has raised concerns among consumers, given their potential negative health effects. Researchers and food industry experts have been exploring plants with potent functional compounds as an alternative source of natural compounds such as anthocyanins, which can be utilized to produce safe food additives. Given their various biological activities, great potential exists for anthocyanins to be used as additives to preserve food or produce functional foods with health benefits. However, to fully realize the economic and health benefits of anthocyanins, a deep understanding of the different plant sources of anthocyanins, as well as their composition, extraction techniques, and function in various products, is warranted. Therefore, this paper critically reviews the different plant sources of anthocyanins and their application in the food and nutraceutical industries, highlighting emerging extraction techniques, health benefits, and challenges in the use of anthocyanins in the food industry. This review also offers insights that could be used in future research and help establish novel and sustainable methods for manufacturing anthocyanin-based value-added products and ingredients.

Influence of mineral fertilizers and liming on the dynamics of CO<sub>2</sub> emissions, crop yield and quality of crop products of crop rotation link

In the field experiment was investigated the effect of repeated lime application on CO2 emissions from the soil, yield and quality of plant products against the background of mineral fertilizers N90P90K90, on dark gray forest heavy loamy soil. As a result of liming and improvement of the acid regime in the soil, prerequisites are created to enhance the vital activity of beneficial microorganisms in the experiment. It was revealed that an increase in biological activity (carbon dioxide emissions) against the background of the application of mineral fertilizers N90P90K90 and CaCO3 ensures high yield and product quality, contributes to favorable conditions for preserving soil fertility and to a greater extent stimulates the development of microorganisms using mineral forms of nitrate nitrogen. With the systematic use of mineral fertilizers N90P90K90 at the stage of crop rotation, an increase in the quality of cultivated crops was noted (the nutritional value of the green mass of clover; the content of crude protein, protein, gluten, starch in barley grain; the nature of grain in winter wheat). In different years of research, according to weather conditions, grain with a high content of crude gluten, protein, nature in winter wheat grain, starch in barley, ash nutrition elements in clover was obtained. The best option turned out to be using dolomite flour and (N90P90K90). All the considered quality indicators of winter wheat improved under the influence of fertilizers and lime, and the difference with the control was: protein – 0,64–1,78%; crude gluten – 1,6–4,3%; grain nature – 11–26 g/l. The highest productivity was obtained when applying mineral fertilizers and lime: barley – 3,53 t/ha, clover hay of the first year of use – 77,53 t/ha, winter wheat – 7,89 t/ha, compared with the control without the use of fertilizers.

Flavonol-Ruthenium Complexes as Antioxidant and Anticancer Agents.

Flavonol-metal complexes can enhance the biological activity of flavonols. Inspired by the potential of ruthenium-based drugs in pharmaceutical applications, seven flavonol-Ru (II) complexes were synthesized to evaluate their biological activities. Among these compounds, compounds 8, 11, and 12 showed potent antioxidant activities. Compound 12 exhibited superior anti-inflammatory activity to natural quercetin, which served as a positive control. This study is the first to report the free radical scavenging abilities and antioxidant activity of flavonol-Ru (II) complexes. Furthermore, compound 12 demonstrated comparable efficacy to 5-FU against human non-small-cell lung cancer cells (A549). These results strongly support the potential of flavonol-Ru (II) agents.

Extracts from the leaves of knotweeds (Reynoutria spp.) have a stimulating effect on the germination and initial growth of wheat grains.

Knotweed (Reynoutria sp.) plants are known in the world mainly as invasive plants. However, it is known that their rhizomes or leaves contain secondary metabolites with biological activity. Our goal was to determine which of the three knotweed plants (Reynoutria japonica, Reynoutria × bohemica, and Reynoutria sachalinensis) is most suitable for seed growth stimulation. We tested alcoholic extracts of all three knotweed species by seed priming method on wheat germination and seedling characteristics, when 12 measured characteristics were monitored. Extracts from all three species of Reynoutria sp. generally showed an improvement in wheat germination and growth compared to the control. R. × bohemica appears to be the best source for stimulating wheat growth, as seedling vigor indexes I and II, R/S dry weight, shoot and seedling lengths, root, shoot, and seedling dry weights were significantly different (ANOVA, Duncan's test, α < 0.05). The plants Reynoutria spp. seem to be possible sources for the protection and stimulation of agriculture crops.

Impact on Human Health of Salmonella spp. and Their Lipopolysaccharides: Possible Therapeutic Role and Asymptomatic Presence Consequences

Epidemiologically, one of the most important concerns associated with introducing Salmonella spp. into the environment and food chain is the presence of asymptomatic carriers. The oncogenic and oncolytic activity of Salmonella and their lipopolysaccharides (LPSs) is important and research on this topic is needed. Even a single asymptomatic dose of the S. Enteritidis LPS (a dose that has not caused any symptoms of illness) in in vivo studies induces the dysregulation of selected cells and bioactive substances of the nervous, immune, and endocrine systems. LPSs from different species, and even LPSs derived from different serotypes of one species, can define different biological activities. The activity of low doses of LPSs derived from three different Salmonella serotypes (S. Enteritidis, S. Typhimurium, and S. Minnesota) affects the neurochemistry of neurons differently in in vitro studies. Studies on lipopolysaccharides from different Salmonella serotypes do not consider the diversity of their activity. The presence of an LPS from S. Enteritidis in the body, even in amounts that do not induce any symptoms of illness, may lead to unknown long-term consequences associated with its action on the cells and biologically active substances of the human body. These conclusions should be important for both research strategies and the pharmaceutical industry &amp;.

Flavin-Catalyzed, Photochemical Conversion of Dehydroalanine into 4,5-Dihydroxynorvaline.

The chemical synthesis of unnatural amino acids (UAA) is a key strategy for preparing designed peptides, including pharmaceutically active compounds. Alterations of existing amino acid residues such as dehydroalanine (Dha) are particularly important since selected positions can be addressed without the necessity of a complete de novo synthesis. The intriguing UAA 4,5-dihydroxynorvaline (Dnv) is found in a variety of naturally occurring peptides and biologically active compounds. However, no method is currently available to modify an existing peptide with this residue. We report the use of flavin catalysts and visible light irradiation for this challenge, which serves as a versatile strategy for converting Dha into Dnv. Our study shows that excited flavins are competent hydrogen atom abstraction catalysts for ethers and acetals, which allows masked 1,2-dihydroxyethylene functionalization from 2,2-dimethyl-1,3-dioxolane. The masked diol was successfully coupled to Dha residues, and a series of Dnv-containing products is reported. A mild and orthogonal protocol for deprotection of the acetal group was also identified, allowing free Dnv-modified peptides to be obtained. This method provides a straightforward strategy for Dnv functionalization, which is envisioned to be crucial for accessing natural products and synthetic analogues with pharmaceutical activity.

A comprehensive analysis of phytochemicals, antioxidant, anti-inflammatory, antibacterial, antifungal and phytoestrogenic properties of different parts of Tribulus terrestris.

Tribulus terrestris L., a medicinal plant rich in secondary metabolites, was studied for optimising bioactive compound extraction from various parts of the plant using ethanol-water (50:50), ethanol, and methanol solvents. Analysis of extracts for key phytochemicals like polyphenols, flavonoids, saponins, and alkaloids was performed using HPTLC, HPLC and gas chromatography. The ethanol-water mixture proved best for extracting saponins and polyphenols, ethanol for flavonoids, and methanol for alkaloids. The fruit yielded the highest saponin content (59.34% ± 3.87), while leaves were richest in polyphenols (18.94% ± 1.39), flavonoids (5.15% ± 1.01), and alkaloids (26.46% ± 1.71). Leaf extracts showed the highest antibacterial activity against B. subtilis and P. aeruginosa, and stem extracts were effective against E. coli. Root, stem, and leaf extracts exhibited antifungal activity with leaf extract also demonstrating strong phytoestrogenic activity. These findings highlight the varied phytochemical profiles and biological activities of T. terrestris, suggesting their potential therapeutic uses.

Design, Synthesis, and Biological Activity Studies of Myricetin Derivatives Containing a Diisopropanolamine Structure.

A series of myricetin derivatives containing diisopropanolamine were designed and synthesized. The in vitro inhibitory effects of the target compounds on 9 fungal pathogens and 3 bacterial pathogens were also evaluated. A12 had the best inhibitory effect against Xanthomonas oryzae pv. oryzae (Xoo), with an EC50 value of 4.9 μg/mL, which was better than zinc-thiazole (ZT: EC50 = 7.3 μg/mL) and thiodiazole-copper (TC: EC50 = 65.5 μg/mL); A25 had the best inhibitory effect against Phomopsis sp. (Ps), with an EC50 value of 17.2 μg/mL, which was better than azoxystrobin (Az: EC50 = 22.3 μg/mL). In vivo inhibition tests were performed on kiwifruit for A25 and rice leaves for A12. At 200 μg/mL, the curative activity of A12 against rice leaf blight was 40.7%, which was better than that of ZT (37.2%) and TC (32.9%), and the protective activity of A12 was 44.8%, which was better than that of ZT (39.5%) and TC (34.6%). The curative activity of A25 against kiwi soft rot disease was 70.1%, which was better than that of Az (62.8%). Preliminary elucidation of the possible mechanisms of action was carried out by experiments on fluorescence microscopy, scanning electron microscopy, formation of biofilms, density functional theory calculations, and so on.

Recognizing primary paleotopography utilizing Ichnofossils and 3-D models: Mill Canyon Dinosaur track site, Utah

Preservation and recognition of primary paleotopography along a bedding surface is often a neglected component in paleogeographic reconstruction. The Mill Canyon Dinosaur track site (MCDT) is a spectacular bedding plane exposure with a diverse assemblage of vertebrate ichnnofauna. Small-scale 3D-photogrammetric and ichnofossil analyses of two areas on the periphery of the MCDT surface demonstrate the presence of preserved primary paleotopography. The first area consists of a paleotopographic bench that drops off to a minimum of ∼0.5–0.6 meters. On this bench is at least one resting trace analogous to modern traces of crocodiles documented from topographic highs along rivers and lakes. At the second locality, systematic variations in track morphology indicate that the trackmaker gait was influenced by changes in surface elevation with movement across the ridge, thus affirming that paleorelief is preserved. The ichnofossils on this Cretaceous bedding surface likely represent months- to years-worth of biological activity.

Exploring Bioactive Fungal RiPPs: Advances, Challenges, and Future Prospects.

Fungal ribosomally synthesized and post-translationally modified peptides (RiPPs) are a vital class of natural products known for their biological activities including anticancer, antitubulin, antinematode, and immunosuppressant properties. These bioactive fungal RiPPs play key roles in chemical ecology and have a significant therapeutic potential. Their structural diversity, which arises from intricate post-translational modifications of precursor peptides, is particularly remarkable. Despite their biological and ecological importance, the discovery of fungal RiPPs has been historically challenging and only a limited number have been identified. To date, known fungal RiPPs are primarily grouped into three groups: cycloamanides and borosins from basidiomycetes and dikaritins from ascomycetes. Recent advancements in bioinformatics have revealed the vast untapped potential of fungi to produce RiPPs, offering new opportunities for their discovery. This review highlights recent progress in fungal RiPP biosynthesis and genome-guided discovery strategies. We propose that combining the knowledge of fungal RiPP biosynthetic pathways with advanced gene-editing technologies and bioinformatic tools will significantly accelerate the discovery of novel bioactive fungal RiPPs.

Evaluating ATP testing for distribution system monitoring: comparison to HPC, impact of chlorine quenching, and hold time dependency.

Adenosine triphosphate (ATP) assays have a faster turnaround time and higher sensitivity than traditional cultivation methods for microbial monitoring. Challenges implementing ATP testing include incompatibility with chlorine quenching agents and hold time sensitivity, which are not well-studied. Chlorinated distribution system samples were collected from two Canadian utilities, Metro Vancouver (n = 40 samples) and Halifax Water (n = 283). No significant correlations were observed between heterotrophic cell count (HPC) and cellular ATP, suggesting these do not correlate well in waters with low biological activity (median HPC < 2CFU/mL). However, interpretation of HPC and cATP results (based on the HPC guideline of 100CFU/mL and cATP of 10pg/mL) yielded the same conclusion for 95% of samples, suggesting a potential decision-making framework to replace HPC with cATP. Moreover, cATP correlates better with free chlorine (p < 0.04) compared with HPC for one of the studied systems. Importantly, adding chlorine quench (10% sodium thiosulfate) did not produce significantly different cATP results, nor did analyzing at various hold times of 4-, 6-, and 24-h. This study supports the integration of ATP testing into existing sampling procedures for water utilities, as a sensitive, fast, and reliable monitoring method.

Comprehensive evaluation of the antibacterial and antibiofilm activities of NiTi orthodontic wires coated with silver nanoparticles and nanocomposites: an in vitro study.

Fixed orthodontic appliances act as a niche for microbial growth and colonization. Coating orthodontic wires with antimicrobial silver nanoparticles (AgNPs) and nanocomposite was adopted in this study to augment the biological activity of these wires by increasing their antibacterial and antibiofilm properties and inhibiting bacterial infections that cause white spot lesions and lead to periodontal disease. Three concentrations of biologically synthesized AgNPs were used for coating NiTi wires. The shape, size, and charge of the AgNPs were determined. Six groups of 0.016 × 0.022-inch NiTi orthodontic wires, each with six wires, were used; and coated with AgNPs and nanocomposites. The antimicrobial and antibiofilm activities of these coated wires were tested against normal flora and multidrug-resistant bacteria (Gram-positive and Gram-negative bacterial isolates). The surface topography, roughness, elemental percentile, and ion release were characterized. AgNPs and nanocomposite coated NiTi wires showed significant antimicrobial and antibiofilm activities. The chitosan-silver nanocomposite (CS-Ag) coated wires had the greatest bacterial growth inhibition against both Gram-positive and Gram-negative bacteria. The surface roughness of the coated wires was significantly reduced, impacting the surface topography and with recorded low Ni and Ag ion release rates. NiTi orthodontic wires coated with AgNPs, and nanocomposites have shown increased antimicrobial and antibiofilm activities, with decreased surface roughness, friction resistance and limited- metal ion release.

The genus Derris Lour., a potential source of valuable biologically active ingredients

AbstractThis article summarizes the recent reports on the chemical components and biological activities of the genus Derris Lour. There are about 240 compounds isolated from this genus, including 31 rotenoids, 146 flavones and their derivatives (flavans, isoflavones, chalcones), 7 triterpenoids, 23 pterocarpans, 10 coumarins, and 34 other compounds. Many compounds have unique structures and exhibit potential biological effects including insecticides, antioxidant, antimicrobial, antifungal, antihyperglycemic, and cytotoxic activities. This review aims to systematically provide research results on the chemical composition and biological activities of Derris species.