Stable Inhibitor Research Articles

COF-SO3H-Catalyzed Synthesis of Pyrazoline-Pyridine Hybrids with Dual Antioxidant and Anti-Inflammatory Activity Targeting PDE4B.

This study explores new anti-inflammatory agents by synthesizing pyrazoline-pyridine hybrids with N-butylsulfonated covalent organic framework (COF-SO3H) as a recyclable catalyst, achieving excellent yields in just one minute. The protocol was successfully scaled up to a multi-gram scale, highlighting its robustness and efficiency, and it operates without the need for column chromatography. Among the synthesized hybrids, compound 5d, a pyrazoline-pyridine hybrid bearing an indole moiety, emerged as a potent anti-inflammatory and antioxidant agent. It effectively inhibited PDE4B activation with an IC50 value of 99.38 nM, without adversely affecting HEK cells. Compound 5d demonstrated its dual activity by significantly reducing ROS production and restoring mitochondrial health in LPS-stimulated A549 and HEK cells, while also downregulating IL-1β and NF-ĸB/p65 expression in LPS-stimulated A549 cells. In silico studies confirmed compound 5d's strong binding to PDE4B, with stable RMSD and RMSF values, indicating its potential as a stable and effective PDE4B inhibitor. The compound exhibited favorable physicochemical properties, met drug-likeness criteria, and showed low toxicity as predicted in silico. These findings suggest that compound 5d has significant potential as a therapeutic agent for inflammatory diseases due to its dual anti-inflammatory and antioxidant activities.

Mirror-Image Random Nonstandard Peptides Integrated Discovery (MI-RaPID) Technology Yields Highly Stable and Selective Macrocyclic Peptide Inhibitors for Matrix Metallopeptidase 7.

Matrix metallopeptidase 7 (MMP7) plays a crucial role in cancer metastasis and progression, making it an attractive target for therapeutic development. However, the development of selective MMP7 inhibitors is challenging due to the conservation of active sites across various matrix metalloproteinases (MMPs). Here, we have developed mirror-image random nonstandard peptides integrated discovery (MI-RaPID) technology to discover innate protease-resistant macrocyclic peptides that specifically bind to and inhibit human MMP7. One identified macrocyclic peptide against D-MMP7, termed D20, was synthesized in its mirror-image form, D'20, consisting of 12 D-amino acids, one cyclic β-amino acid, and a thioether bond. Notably, it potently inhibited MMP7 with an IC50 value of 90 nM, and showed excellent selectivity over other MMPs with similar substrate specificity. Moreover, D'20 inhibited the migration of pancreatic cell line CFPAC-1, but had no effect on the cell proliferation and viability. D'20 exhibited excellent stability in human serum, as well as in simulated gastric and intestinal fluids. This study highlights that MI-RaPID technology can serve as a powerful tool to develop in vivo stable macrocyclic peptides for therapeutic applications.

Mirror‐Image Random Nonstandard Peptides Integrated Discovery (MI‐RaPID) Technology Yields Highly Stable and Selective Macrocyclic Peptide Inhibitors for Matrix Metallopeptidase 7

AbstractMatrix metallopeptidase 7 (MMP7) plays a crucial role in cancer metastasis and progression, making it an attractive target for therapeutic development. However, the development of selective MMP7 inhibitors is challenging due to the conservation of active sites across various matrix metalloproteinases (MMPs). Here, we have developed mirror‐image random nonstandard peptides integrated discovery (MI‐RaPID) technology to discover innate protease‐resistant macrocyclic peptides that specifically bind to and inhibit human MMP7. One identified macrocyclic peptide against D‐MMP7, termed D20, was synthesized in its mirror‐image form, D’20, consisting of 12 D‐amino acids, one cyclic β‐amino acid, and a thioether bond. Notably, it potently inhibited MMP7 with an IC50 value of 90 nM, and showed excellent selectivity over other MMPs with similar substrate specificity. Moreover, D’20 inhibited the migration of pancreatic cell line CFPAC‐1, but had no effect on the cell proliferation and viability. D’20 exhibited excellent stability in human serum, as well as in simulated gastric and intestinal fluids. This study highlights that MI‐RaPID technology can serve as a powerful tool to develop in vivo stable macrocyclic peptides for therapeutic applications.

Synthesis and Molecular Docking of Curcumin-Derived Pyrazole-Thiazole Hybrids as Potent α-Glucosidase Inhibitors.

α Glucosidase inhibitors are critical for diabetes management, with pyrazoles and thiazoles emerging as effective options. This research highlights curcumin-based pyrazole-thiazole hybrids as potential inhibitors, synthesizing derivatives and evaluating their inhibitory capabilities. The study involved the synthesis of novel compounds using hydrazonoyl halides, confirmed through elemental and spectral analyses. The synthesized derivatives exhibited significant α-glucosidase inhibition, with IC50 values ranging from 3.37 ± 0.25 to 16.35 ± 0.37 µM. Among them, compound 7e demonstrated the strongest inhibition at 3.37 ± 0.25 µM, outperforming the standard drug acarbose (IC50 = 5.36 ± 0.31 µM). In silico assessments and molecular docking using AutoDock Vina revealed strong interactions, particularly with compounds 7b, 7e, 7f, and 7g, indicating their potential as stable and effective inhibitors. The results suggest that the synthesized pyrazole-thiazole hybrids hold promise as novel therapeutic agents for diabetes, warranting further exploration of their substituent effects for optimized inhibitor design.

Overcoming Irinotecan Resistance by Targeting Its Downstream Signaling Pathways in Colon Cancer

Among the most popular chemotherapeutic agents, irinotecan, regarded as a prodrug belonging to the camptothecin family that inhibits topoisomerase I, is widely used to treat metastatic colorectal cancer (CRC). Although immunotherapy is promising for several cancer types, only microsatellite-instable (~7%) and not microsatellite-stable CRCs are responsive to it. Therefore, it is important to investigate the mechanism of irinotecan function to identify cellular proteins and/or pathways that could be targeted for combination therapy. Here, we have determined the effect of irinotecan treatment on the expression/activation of tumor suppressor genes (including p15Ink4b, p21Cip1, p27Kip1, and p53) and oncogenes (including OPN, IL8, PD-L1, NF-κB, ISG15, Cyclin D1, and c-Myc) using qRT-PCR, Western blotting, immunofluorescence (IF), and RNA sequencing of tumor specimens. We employed stable knockdown, neutralizing antibodies (Abs), and inhibitors of OPN, p53, and NF-κB to establish downstream signaling and sensitivity/resistance to the cytotoxic activities of irinotecan. Suppression of secretory OPN and NF-κB sensitized colon cancer cells to irinotecan. p53 inhibition or knockdown was not sufficient to block or potentiate SN38-regulated signaling, suggesting p53-independent effects. Irinotecan treatment inhibited tumor growth in syngeneic mice. Analyses of allograft tumors from irinotecan-treated mice validated the cell culture results. RNA-seq data suggested that irinotecan-mediated activation of NF-κB signaling modulated immune and inflammatory genes in mice, which may compromise drug efficacy and promote resistance. In sum, these results suggest that, for CRCs, targeting OPN, NF-κB, PD-L1, and/or ISG15 signaling may provide a potential strategy to overcome resistance to irinotecan-based chemotherapy.

Selective inhibition of HDAC class IIA as therapeutic intervention for KMT2A-rearranged acute lymphoblastic leukemia

KMT2A-rearranged acute lymphoblastic leukemia (ALL) is characterized by deregulation of the epigenome and shows susceptibility towards histone deacetylase (HDAC) inhibition. Most broad-spectrum HDAC inhibitors simultaneously target multiple human HDAC isoforms. Consequently, they often induce toxicity and especially in combination with other therapeutic agents. Therefore, more specifically targeting HDAC isoforms may represent a safer therapeutic strategy. Here we show that shRNA-mediated knock-down of the class IIA HDAC isoforms HDAC4, HDAC5, and HDAC7 results in apoptosis induction and cell cycle arrest in KMT2A-rearranged ALL cells. In concordance, the HDAC4/5 selective small molecule inhibitor LMK-235 effectively eradicates KMT2A-rearranged ALL cell lines as well as primary patient samples in vitro. However, using a xenograft mouse model of KMT2A-rearranged ALL we found that the maximum achievable dose of LMK-235 was insufficient to induce anti-leukemic effects in vivo. Similar results were obtained for the specific class IIA HDAC inhibitors MC1568 and TMP195. Finally, LMK-235 appeared to exert minimal anti-leukemic effects in vivo in combination with the BCL-2 inhibitor venetoclax, but not enough to prolong survival in treated mice. In conclusion, class IIA HDAC isoforms represent attractive therapeutic target in KMT2A-rearranged ALL, although clinical applications require the development of more stable and efficient specific HDAC inhibitors.

Kaempferol as a novel inhibitor of SARS-CoV-2 RNA-dependent RNA polymerase

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has quickly become a global health pandemic. Among the viral proteins, RNA‐dependent RNA polymerase (RdRp) is responsible for viral genome replication and has emerged as a promising target against SARS‐CoV‐2 infection. Dietary bioactive compounds represent an important source of evolutionarily optimized molecules with antiviral properties against SARS-CoV-2 RdRp. We investigated the inhibitory potential effects of different phytochemicals against SARS-CoV-2 RdRp, including andrographolide, kaempferol, resveratrol, and silibinin. Unlike the other investigated compounds, kaempferol exhibited a significant dose-dependent in vitro inhibition of SARS-CoV-2 RdRp activity. To assess the binding interactions and stability of the SARS-CoV-2 RdRp-kaempferol complex, we performed in silico techniques, including molecular docking, quantum chemical calculation, and molecular dynamics simulations. We found strong binding affinities and stability between kaempferol and SARS-CoV-2 RdRp variants (Wuhan and Omicron). These findings provide valuable insights into the antiviral properties of kaempferol as a stable inhibitor of SARS-CoV-2 RdRp. Communicated by Ramaswamy H. Sarma

Peptidomimetic inhibitors of the VEGF-A165/NRP-1 complex obtained by modification of the C-terminal arginine

Inhibitors of the interaction between Neuropilin-1 (NRP-1) and Vascular Endothelial Growth Factor-A165 (VEGF-A165) hold significant promise as therapeutic and diagnostic agents directed against cancers overexpressing NRP-1. In our efforts in this field, a few series of strong and fairly stable peptide-like inhibitors of the general formula Lys(Har)1-Xaa2-Xaa3-Arg4 have been previously discovered. In the current work, we focused on Lys(Har)-Dap/Dab-Pro-Arg sequence. The aim was to examine whether replacing C-terminal Arg with its homologs and mimetics would yield more stable yet still potent inhibitors. Upon considering the results of modelling and other factors, ten novel analogues with Xaa4 = homoarginine (Har), 2-amino-4-guanidino-butyric acid (Agb), 2-amino-3-guanidino-propionic acid (Agp), citrulline (Cit), 4-aminomethyl-phenylalanine [Phe(4-CH2-NH2)] were designed, synthesized and evaluated. Two of the proposed modifications resulted in inhibitors with activity slightly lower [e.g. IC50 = 14.3 μM for Lys(Har)-Dab-Pro-Har and IC50 = 19.8 μM for Lys(Har)-Dab-Pro-Phe(4-CH2-NH2)] than the parent compounds [e.g. IC50 = 4.7 μM for Lys(Har)-Dab-Pro-Arg]. What was a surprise to us, the proteolytic stability depended more on position two of the sequence than on position four. The Dab2-analogues exhibited half-life times beyond 60 h. Our results build up the knowledge on the structural requirements that effective VEGF-A165/NRP-1 inhibitors should fulfil.

Effectiveness of expired estradiol valerate drug molecule as a corrosion inhibitor for mild steel in 1 M HCl medium: Waste utilization perspective

This study explores the utilization of expired pharmaceutical drugs, specifically Progynova 2 mg (estradiol valerate), as a sustainable solution for corrosion inhibition in mild steel exposed to a 1 M HCl medium at 30 °C. Through a comprehensive analysis employing FTIR, mass loss, potentiodynamic polarization, electrochemical impedance spectroscopy (EIS), quantum chemical analysis (DFT), and scanning electron microscopy (SEM), the research confirms the remarkable effectiveness of estradiol valerate (EPROG) in inhibiting mild steel corrosion, achieving an impressive 94.27 % inhibition efficiency at a concentration of 600 ppm. Potentiodynamic polarization reveals mixed-type inhibition behavior, while EIS measurements indicate increased charge transfer resistance (Rct) and reduced double layer capacity (Cdl) with higher estradiol valerate concentrations, in line with Langmuir adsorption isotherm results. The DFT analysis of the EPROG inhibitor indicates that it use a donor-acceptor mechanism to interact with the metal surface. SEM analysis further substantiates the presence of a stable EPROG inhibitor layer on the mild steel surface, underscoring its corrosion inhibition properties and advocating for the sustainable repurposing of expired pharmaceuticals in environmental and structural preservation efforts.

Structure-Activity Relationship Studies of Aryl Sulfoxides as Reversible Monoacylglycerol Lipase Inhibitors.

Monoacylglycerol lipase (MAGL) is the key enzyme for the hydrolysis of endocannabinoid 2-arachidonoylglycerol (2-AG). The central role of MAGL in the metabolism of 2-AG makes it an attractive therapeutic target for a variety of disorders, including inflammation-induced tissue injury, pain, multiple sclerosis, and cancer. Previously, we reported LEI-515, an aryl sulfoxide, as a peripherally restricted, covalent reversible MAGL inhibitor that reduced neuropathic pain and inflammation in preclinical models. Here, we describe the structure-activity relationship (SAR) of aryl sulfoxides as MAGL inhibitors that led to the identification of LEI-515. Optimization of the potency of high-throughput screening (HTS) hit 1 yielded compound ±43. However, ±43 was not metabolically stable due to its ester moiety. Replacing the ester group with α-CF2 ketone led to the identification of compound ±73 (LEI-515) as a metabolically stable MAGL inhibitor with subnanomolar potency. LEI-515 is a promising compound to harness the therapeutic potential of MAGL inhibition.

Expression and antiviral application of exogenous lectin (griffithsin) in sweetpotatoes.

Griffithsin (GRFT) is a highly effective, broad-spectrum, safe, and stable viral inhibitor used to suppress a variety of viruses. However, little information is available on whether GRFT can prevent plant viral diseases. In this study, we constructed a GRFT overexpression vector containing the sweetpotato storage cell signal peptide and generated exogenous GRFT overexpression lines through genetic transformation. The transgenic plants showed notable resistance to sweetpotato virus disease in the virus nursery. To verify the antiplant virus function of GRFT, transient expression in tobacco leaves showed that GRFT inhibited the sweetpotato leaf curl virus (SPLCV). The replication of SPLCV was entirely inhibited when the concentration of GRFT reached a certain level. The results of pulldown and BIFC assays showed that GRFT did not interact with the six components of SPLCV. In addition, the mutated GRFTD/A without the binding ability of carbohydrate and anticoronavirus function, in which three aspartate residues at carbohydrate binding sites were all mutated to alanine, also inhibited SPLCV. Quantitative reverse-transcription PCR analyses showed that the tobacco antiviral-related genes HIN1, ICS1, WRKY40, and PR10 were overexpressed after GRFT/GRFTD/A injection. Furthermore, HIN1, ICS1, and PR10 were more highly expressed in the leaves injected with GRFTD/A. The results suggest that sweetpotato is able to express GRFT exogenously as a bioreactor. Moreover, exogenous GRFT expression inhibits plant viruses by promoting the expression of plant antiviral genes.

Insights into Allosteric Inhibition of the AcrB Efflux Pump: Role of Distinct Binding Pockets, Protomer Preferences, and Crosstalk Disruption.

AcrB, a key component in bacterial efflux processes, exhibits distinct binding pockets that influence inhibitor interactions. In addition to the well-known distal binding pocket within the periplasmic domain, a noteworthy pocket amidst the transmembrane (TM) helices serves as an alternate binding site for inhibitors. The bacterial efflux mechanism involves a pivotal functional rotation of the TM protein, inducing conformational changes in each protomer and propelling drugs toward the outer membrane domain. Surprisingly, inhibitors binding to the TM domain display a preference for L protomers over T protomers. Metadynamics simulations elucidate that Lys940 in the TM domain of AcrB can adopt two conformations in L protomers, whereas the energy barrier for such transitions is higher in T protomers. This phenomenon results in stable inhibitor binding in l protomers. Upon a detailed analysis of unbinding pathways using random accelerated molecular dynamics and umbrella sampling, we have identified three distinct routes for ligand exit from the allosteric site, specifically involving regions within the TM domains─TM4, TM5, and TM10. To explore allosteric crosstalk, we focused on the following key residues: Val452 from the TM domain and Ala831 from the porter domain. Surprisingly, our findings reveal that inhibitor binding disrupts this communication. The shortest path connecting Val452 and Ala831 increases upon inhibitor binding, suggesting sabotage of the natural interdomain communication dynamics. This result highlights the intricate interplay between inhibitor binding and allosteric signaling within our studied system.

A diverse proteome is present and enzymatically active in metabolite extracts

Metabolite extraction is the critical first-step in metabolomics experiments, where it is generally regarded to inactivate and remove proteins. Here, arising from efforts to improve extraction conditions for polar metabolomics, we discover a proteomic landscape of over 1000 proteins within metabolite extracts. This is a ubiquitous feature across several common extraction and sample types. By combining post-resuspension stable isotope addition and enzyme inhibitors, we demonstrate in-extract metabolite interconversions due to residual transaminase activity. We extend these findings with untargeted metabolomics where we observe extensive protein-mediated metabolite changes, including in-extract formation of glutamate dipeptide and depletion of total glutathione. Finally, we present a simple extraction workflow that integrates 3 kDa filtration for protein removal as a superior method for polar metabolomics. In this work, we uncover a previously unrecognized, protein-mediated source of observer effects in metabolomics experiments with broad-reaching implications across all research fields using metabolomics and molecular metabolism.

Evaluation of green corrosion inhibitors of chitosan oligosaccharide derivatives for CO2 corrosion inhibition on 20# carbon steel

Two chitosan oligosaccharide derivatives, VCOS and GCOS, were synthesized and explored as corrosion inhibitors, the synergistic inhibition effect of KI and VCOS was also studied. Their structures were elucidated using Fourier Transform Infrared Spectroscopy and Nuclear Magnetic Resonance. The inhibition efficacy of VCOS+KI and GCOS on 20# steel within an 80℃, 3 wt% NaCl, CO2-saturated solution system was investigated employing various techniques, including gravimetric measurement, electrochemical analysis, Scanning Electron Microscopy (SEM), Atomic Force Microscopy (AFM), and molecular dynamics simulations. The results reveal that the inhibition efficiency of VCOS is relatively low when it acts alone. When VCOS and KI are combined, they have a good synergistic effect, and the synergistic parameter is the highest at 6.209. In the weight loss experiment, the corrosion inhibition efficiency increased with the concentration of the corrosion inhibitor. The inhibition rates of VCOS+KI and GCOS were 90.5 % and 90.2 %, respectively. The adsorption on 20# steel conformed to the Langmuir isotherm adsorption equation. The measurement results of SEM, Energy Dispersive Spectroscopy, and AFM show that VCOS+KI and GCOS adsorbed on the surface of carbon steel to form a dense inhibitor film, which effectively protected the metal substrate. According to the polarization test results, both VCOS+KI and GCOS are mixed-type inhibitors primarily exhibiting anodic inhibition, with inhibition efficiencies reaching 98.9 % and 95.1 %, respectively. Electrochemical impedance spectroscopy tests showed that with increasing inhibitor concentration and immersion time, Rct increased and Cdl decreased, resulting in a gradual increase in inhibition efficiency and the formation of a dense and stable inhibitor film. The results indicate that VCOS+KI and GCOS are non-toxic, water-soluble, and environmentally friendly inhibitors with good anti-corrosion performance.

De novo design of covalent bonding peptides for target protein

To rapidly develop hyper-stable inhibitors that bind specifically and covalently to functional proteins is critical for diagnostics and therapeutics. Taking targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants as an example, we report a fast and low-cost de novo design strategy on covalent bonding peptides toward the SARS-CoV-2 spike protein receptor-binding domain (RBD), hence blocking its interaction with the human angiotensin-converting enzyme 2 (hACE2). As a proof-of-concept, peptide scaffolds built by ligating the hotspot residues at the hACE2-Omicron RBD interface were docked against RBD, and then the chemically modified peptides were designed by predicting their reactivity against RBD using a modified Amber ff14SB force field. Two peptides (15- and 16-mer peptides) were equipped with sulfonyl fluoride warheads bound with the conserved Y449 residue of RBD via the sulfur (VI) fluoride exchange (SuFEx) click chemistry. With permanent bonding and without dissociation, the two peptides blocked Omicron BA.2 pseudovirus infection with IC50 values of 1.07 μM and 1.56 μM, respectively. Our design approach greatly promotes the discovery of hyper-stable inhibitors against SARS-CoV-2 variants and other rapidly evolving viruses, potentially applicable to combat future viral outbreaks efficiently.

Identification of vilazodone as a novel plasminogen activator inhibitor to overcome Alzheimer's disease through virtual screening, molecular dynamics simulation, and biological evaluation.

Urokinase-type plasminogen activator (PLAU), a member of the S1 serine peptidase family in Clan PA, plays a crucial role in the conversion of plasminogen into active plasmin. However, the precise role of PLAU in the central nervous system remains incompletely elucidated, particularly, in relation to Alzheimer's disease (AD). In this study, we successfully identified that PLAU could promote cell senescence in neurons, indicating it as a potential target for ADtreatment through a systematic approach, which included both bioinformatics analysis and experimental verification. Subsequently, a structure-based virtual screening approach was employed to identify a potential PLAU inhibitor from theFood and Drug Administration-approved drug database. After analyzing docking scores and thoroughly examining the receptor-ligand complex interaction modes, vilazodone emerges as a highly promising PLAU inhibitor. Additionally, molecular docking and molecular dynamics simulations were performed to generate a complex structure between the relatively stable inhibitor vilazodone and PLAU. Of note, vilazodone exhibited superior cytotoxicity against senescent cells, showing a senolytic activity through targeting PLAU and ultimately producing an anti-AD effect. These findings suggest that targeting PLAU could represent a promising therapeutic strategy for AD. Furthermore, investigating the inhibitory potential and structural modifications based on vilazodone may provide valuable insights for future drug development targeting PLAU in AD disorders.

Investigating Potential Cancer Therapeutics: Insight into Histone Deacetylases (HDACs) Inhibitions.

Histone deacetylases (HDACs) are enzymes that remove acetyl groups from ɛ-amino of histone, and their involvement in the development and progression of cancer disorders makes them an interesting therapeutic target. This study seeks to discover new inhibitors that selectively inhibit HDAC enzymes which are linked to deadly disorders like T-cell lymphoma, childhood neuroblastoma, and colon cancer. MOE was used to dock libraries of ZINC database molecules within the catalytic active pocket of target HDACs. The top three hits were submitted to MD simulations ranked on binding affinities and well-occupied interaction mechanisms determined from molecular docking studies. Inside the catalytic active site of HDACs, the two stable inhibitors LIG1 and LIG2 affect the protein flexibility, as evidenced by RMSD, RMSF, Rg, and PCA. MD simulations of HDACs complexes revealed an alteration from extended to bent motional changes within loop regions. The structural deviation following superimposition shows flexibility via a visual inspection of movable loops at different timeframes. According to PCA, the activity of HDACs inhibitors induces structural dynamics that might potentially be utilized to define the nature of protein inhibition. The findings suggest that this study offers solid proof to investigate LIG1 and LIG2 as potential HDAC inhibitors.

Novel Stable Protease Inhibitor from Phoenix dactylifera(L.) Flowers with Antimicrobial and Antitumoral Activities.

A novel protease inhibitor isolated from date palm Phoenix dactylifera(L.) flowers (PIDF) was purified and characterized. A heat and acidic treatment step followed by ethanol precipitation and reverse-phase high-performance chromatography was applied to purify this natural protease inhibitor to homogeneity with a single band of about 19 kDa. The stability study depicted that PIDF was fully stable at 40 °C and retained 65% of its initial activity after heating at 50 °C for 24 h. Its thermal stability at 70 °C was markedly enhanced by adding calcium, bovine serum albumin, and sorbitol as well as by metal divalent cations, especially Mg2+ and Hg2+. This protease inhibitor showed high inhibitory activity against therapeutic proteases, including pepsin, trypsin, chymotrypsin, and collagenase, and acted as a potent inhibitor of some commercial microbial proteases from Aspergillus oryzae, Bacillus. sp, and Bacillus licheniformis. Moreover, a potent antibacterial spectrum against Gram (+) and Gram (-) bacterial strains and an efficient antifungal effect were observed. Its cytotoxicity toward human colorectal cancer cell LoVo and HCT-116 lines suggested that PIDF could serve as a new therapeutic target inhibiting human colorectal cancer.

Targeting the proteases of arboviruses with cyclic and bicyclic peptides

Arthropod-borne (arbo) viruses infect hundreds of millions of people annually. Many arboviruses and their mosquito vectors circulate in Australia and neighbouring regions. Recent years have shown that explosive outbreaks accompanied by life-threating symptoms such as encephalitis are unpredictable and increasingly common, particularly due to the effects of climate change. Two major genera of pathogenic viruses are flaviviruses and alphaviruses. Both require their own viral proteases to replicate and infect new cells. Viral proteases can be considered the Achilles heel of replication and are already long-established drug targets in the fight against chronic viral infectious diseases, for example, HIV/AIDS. We developed a large variety of high-affinity and proteolytically stable peptide inhibitors of flaviviral proteases using innovative chemical approaches. Our chemical strategies proceed under biocompatible conditions, enabling in situ access to constrained peptide ligands in presence of proteases and other drug targets. While cyclic and bicyclic peptides offer many advantages over small molecules used in conventional drug discovery, their limited bioavailability is a major challenge that still needs to be overcome.

The anticancer potential of chemical constituents of Moringa oleifera targeting CDK-2 inhibition in estrogen receptor positive breast cancer using in-silico and in vitro approches

Most of the breast cancers are estrogen receptor-positive recurring with a steady rate of up to 20 years dysregulating the normal cell cycle. Dinaciclib is still in clinical trials and considered as a research drug against such cancers targeting CDK2.The major goal of this study was to identify the potential inhibitors of CDK-2 present in Moringa oleifera for treating hormonal receptor positive breast cancers. For this purpose, in silico techniques; molecular docking, MM-GBSA and molecular dynamics simulations were employed to screen Moringa oleifera compounds and their anticancer potential was determined against CDK-2 protein targets. Among 36 compounds of Moringa oleifera reported in literature, chlorogenic acid (1), quercetin (2), ellagic acid (3), niazirin (4), and kaempferol (5) showed good affinity with the target. The interaction of the compounds was visualized using PYMOL software. The profiles of absorption, distribution, metabolism, excretion (ADME) and toxicity were determined using SWISS and ProTox II webservers. The MTT assay was performed in-vitro using MCF-7 cancer cell lines to validate the anticancer potential of Moringa oleifera leaf extract.MTT assay results revealed no significant change in proliferation of Mcf-7 cells following 24 h treatment with fraction A (petroleum ether). However, significant antiproliferative effect was observed at 200 µg/mL dose of fraction B (ethyl acetate) and cell viability was reduced to 40%.In conclusion, the data suggested that all the compounds with highest negative docking score than the reference could be the potential candidates for cyclin dependent kinase-2 (CDK-2) inhibition while ellagic acid, chlorogenic acid and quercetin being the most stable and potent inhibitors to treat estrogen receptor positive breast cancer targeting CDK-2. Moreover, the data suggested that further investigation is required to determine the optimum dose for significant antiproliferative effects using in-vivo models to validate our findings of in-silico analysis.