Biomedicines

Editorial

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6 pages, 227 KiB

Open AccessEditorial

Recent Advances in the Discovery of Novel Drugs on Natural Molecules

by Laura Quintieri, Leonardo Caputo and Orazio Nicolotti

Biomedicines 2024, 12(6), 1254; https://doi.org/10.3390/biomedicines12061254 - 5 Jun 2024

Cited by 1 | Viewed by 1297

Abstract

Natural products (NPs) are always a promising source of novel drugs for tackling unsolved diseases [...] Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

Research

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17 pages, 3347 KiB

Open AccessArticle

Tanshinone IIA Facilitates Efficient Cartilage Regeneration under Inflammatory Factors Caused Stress via Upregulating LncRNA NEAT1_2

by Jingjing Sun, Wei Chen, Zheng Zhou, Xin Chen, You Zuo, Jiaqian He and Hairong Liu

Biomedicines 2023, 11(12), 3291; https://doi.org/10.3390/biomedicines11123291 - 12 Dec 2023

Cited by 3 | Viewed by 1369

Abstract

(1) Background: Osteoarthritis (OA) is a crippling condition characterized by chondrocyte dedifferentiation, cartilage degradation, and subsequent cartilage defects. Unfortunately, there is a lack of effective medicines to facilitate the repair of cartilage defects in OA patients. In this study, we investigated the role [...] Read more.

(1) Background: Osteoarthritis (OA) is a crippling condition characterized by chondrocyte dedifferentiation, cartilage degradation, and subsequent cartilage defects. Unfortunately, there is a lack of effective medicines to facilitate the repair of cartilage defects in OA patients. In this study, we investigated the role of lncRNA NEAT1_2 in maintaining the chondrocyte phenotype and identified tanshinone IIA(TAN) as a natural medicine that enhances NEAT1_2 levels, resulting in efficient cartilage regeneration under inflammatory cytokines. (2) Methods: The transcriptional levels of NEAT1_2 and cartilage phenotype-related genes were identified by RT-qPCR. The siRNA interference approach was utilized to silence NEAT1_2; the Alamar Blue assay was performed to determine chondrocyte viability under inflammatory conditions. To evaluate the concentrations of collagen type II and glycosaminoglycans distributed by chondrocytes in vitro and in vivo, immunohistochemical staining and Safranin O staining were used. (3) Results: IL-1β suppresses NEAT1_2 and genes related to the chondrocytic phenotype, whereas TAN effectively upregulates them in a NEAT1_2-dependent manner. Consistently, TAN alleviated chondrocyte oxidative stress inhibited cartilage degradation by modulating the relevant genes and promoted efficient cartilage regeneration in vitro and in vivo when chondrocytes are exposed to inflammatory cytokines. (4) Conclusions: TAN enhances the expression of NEAT1_2 inhibited by IL-1β and affects the transcription of chondrocytic phenotype-related genes, which promotes cartilage regeneration in an inflammatory environment. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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16 pages, 2674 KiB

Open AccessArticle

Identification of the Natural Steroid Sapogenin Diosgenin as a Direct Dual-Specific RORα/γ Inverse Agonist

by Patrik F. Schwarz, Alexander F. Perhal, Lucia N. Schöberl, Martin M. Kraus, Johannes Kirchmair and Verena M. Dirsch

Biomedicines 2022, 10(9), 2076; https://doi.org/10.3390/biomedicines10092076 - 25 Aug 2022

Cited by 5 | Viewed by 2964

Abstract

The steroid sapogenin diosgenin is a well-known natural product with a plethora of described pharmacological activities including the amelioration of T helper 17 (Th17)-driven pathologies. However, the exact underlying mode of action of diosgenin leading to a dampened Th17 response is still largely [...] Read more.

The steroid sapogenin diosgenin is a well-known natural product with a plethora of described pharmacological activities including the amelioration of T helper 17 (Th17)-driven pathologies. However, the exact underlying mode of action of diosgenin leading to a dampened Th17 response is still largely unknown and specific molecular targets have yet to be identified. Here, we show that diosgenin acts as a direct ligand and inverse agonist of the nuclear receptor retinoic acid receptor (RAR)-related orphan receptor (ROR)α and RORγ, which are key transcription factors involved in Th17 cell differentiation and metabolism. IC₅₀ values determined by luciferase reporter gene assays, employing constructs for either RORγ-Gal4 fusion proteins or full length receptors, were in the low micromolar range at around 2 µM. To highlight the functional consequences of this RORα/γ inverse agonism, we determined gene expression levels of important ROR target genes, i.e., IL-17A and glucose-6-phosphatase, in relevant cellular in vitro models of Jurkat T and HepG2 cells, respectively, by RT-qPCR (reverse transcription quantitative PCR). Thereby, it was shown that diosgenin leads to a dose-dependent decrease in target gene expressions consistent with its potent cellular ROR inverse agonistic activity. Additionally, in silico dockings of diosgenin to the ROR ligand-binding domain were performed to determine the underlying binding mode. Taken together, our results establish diosgenin as a novel, direct and dual-selective RORα/γ inverse agonist. This finding establishes a direct molecular target for diosgenin for the first time, which can further explain reported amendments in Th17-driven diseases by this compound. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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11 pages, 593 KiB

Open AccessArticle

Rational Discovery of Antiviral Whey Protein-Derived Small Peptides Targeting the SARS-CoV-2 Main Protease

by Nicola Gambacorta, Leonardo Caputo, Laura Quintieri, Linda Monaci, Fulvio Ciriaco and Orazio Nicolotti

Biomedicines 2022, 10(5), 1067; https://doi.org/10.3390/biomedicines10051067 - 4 May 2022

Cited by 11 | Viewed by 2713

Abstract

In the present work, and for the first time, three whey protein-derived peptides (IAEK, IPAVF, MHI), endowed with ACE inhibitory activity, were examined for their antiviral activity against the SARS-CoV-2 3C-like protease (3CL^pro) and Human Rhinovirus 3C protease (3C^pro) [...] Read more.

In the present work, and for the first time, three whey protein-derived peptides (IAEK, IPAVF, MHI), endowed with ACE inhibitory activity, were examined for their antiviral activity against the SARS-CoV-2 3C-like protease (3CL^pro) and Human Rhinovirus 3C protease (3C^pro) by employing molecular docking. Computational studies showed reliable binding poses within 3CL^pro for the three investigated small peptides, considering docking scores as well as the binding free energy values. Validation by in vitro experiments confirmed these results. In particular, IPAVF exhibited the highest inhibitory activity by returning an IC₅₀ equal to 1.21 μM; it was followed by IAEK, which registered an IC₅₀ of 154.40 μM, whereas MHI was less active with an IC₅₀ equal to 2700.62 μM. On the other hand, none of the assayed peptides registered inhibitory activity against 3C^pro. Based on these results, the herein presented small peptides are introduced as promising molecules to be exploited in the development of “target-specific antiviral” agents against SARS-CoV-2. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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24 pages, 8799 KiB

Open AccessArticle

KasQ an Epimerase Primes the Biosynthesis of Aminoglycoside Antibiotic Kasugamycin and KasF/H Acetyltransferases Inactivate Its Activity

by Rajesh Rattinam, R. Sidick Basha, Yung-Lin Wang, Zhe-Chong Wang, Ning-Shian Hsu, Kuan-Hung Lin, Saeid Malek Zadeh, Kamal Adhikari, Jin-Ping Lin and Tsung-Lin Li

Biomedicines 2022, 10(2), 212; https://doi.org/10.3390/biomedicines10020212 - 19 Jan 2022

Cited by 3 | Viewed by 3195

Abstract

Kasugamycin (KSM), an aminoglycoside antibiotic, is composed of three chemical moieties: D-chiro-inositol, kasugamine and glycine imine. Despite being discovered more than 50 years ago, the biosynthetic pathway of KSM remains an unresolved puzzle. Here we report a structural and functional analysis [...] Read more.

Kasugamycin (KSM), an aminoglycoside antibiotic, is composed of three chemical moieties: D-chiro-inositol, kasugamine and glycine imine. Despite being discovered more than 50 years ago, the biosynthetic pathway of KSM remains an unresolved puzzle. Here we report a structural and functional analysis for an epimerase, KasQ, that primes KSM biosynthesis rather than the previously proposed KasF/H, which instead acts as an acetyltransferase, inactivating KSM. Our biochemical and biophysical analysis determined that KasQ converts UDP-GlcNAc to UDP-ManNAc as the initial step in the biosynthetic pathway. The isotope-feeding study further confirmed that ¹³C, ¹⁵N-glucosamine/UDP-GlcNH₂ rather than glucose/UDP-Glc serves as the direct precursor for the formation of KSM. Both KasF and KasH were proposed, respectively, converting UDP-GlcNH₂ and KSM to UDP-GlcNAc and 2-N’-acetyl KSM. Experimentally, KasF is unable to do so; both KasF and KasH are instead KSM-modifying enzymes, while the latter is more specific and reactive than the former in terms of the extent of resistance. The information gained here lays the foundation for mapping out the complete KSM biosynthetic pathway. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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24 pages, 5011 KiB

Open AccessArticle

Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B Inhibitors

by Vedanjali Gogineni, Manal A. Nael, Narayan D. Chaurasiya, Khaled M. Elokely, Christopher R. McCurdy, John M. Rimoldi, Stephen J. Cutler, Babu L. Tekwani and Francisco León

Biomedicines 2021, 9(10), 1304; https://doi.org/10.3390/biomedicines9101304 - 24 Sep 2021

Cited by 7 | Viewed by 3132

Abstract

A series of dietary flavonoid acacetin 7-O-methyl ether derivatives were computationally designed aiming to improve the selectivity and potency profiles against monoamine oxidase (MAO) B. The designed compounds were evaluated for their potential to inhibit human MAO-A and -B. Compounds 1c [...] Read more.

A series of dietary flavonoid acacetin 7-O-methyl ether derivatives were computationally designed aiming to improve the selectivity and potency profiles against monoamine oxidase (MAO) B. The designed compounds were evaluated for their potential to inhibit human MAO-A and -B. Compounds 1c, 2c, 3c, and 4c were the most potent with a Ki of 37 to 68 nM against MAO-B. Compounds 1c–4c displayed more than a thousand-fold selectivity index towards MAO-B compared with MAO-A. Moreover, compounds 1c and 2c showed reversible inhibition of MAO-B. These results provide a basis for further studies on the potential application of these modified flavonoids for the treatment of Parkinson’s Disease and other neurological disorders. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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13 pages, 2730 KiB

Open AccessArticle

A Novel Competitive Binding Screening Assay Reveals Sennoside B as a Potent Natural Product Inhibitor of TNF-α

by Lei Peng, Prasannavenkatesh Durai, Keunwan Park, Jeong Joo Pyo and Yongsoo Choi

Biomedicines 2021, 9(9), 1250; https://doi.org/10.3390/biomedicines9091250 - 17 Sep 2021

Cited by 3 | Viewed by 2747

Abstract

Natural products (NPs) have played a significant role in drug discovery for diverse diseases, and numerous attempts have been made to discover promising NP inhibitors of tumor necrosis factor α (TNF-α), a major therapeutic target in autoimmune diseases. However, NP inhibitors of TNF-α, [...] Read more.

Natural products (NPs) have played a significant role in drug discovery for diverse diseases, and numerous attempts have been made to discover promising NP inhibitors of tumor necrosis factor α (TNF-α), a major therapeutic target in autoimmune diseases. However, NP inhibitors of TNF-α, which have the potential to be developed as new drugs, have not been reported for over a decade. To facilitate the search for new promising inhibitors of TNF-α, we developed an efficient competitive binding screening assay based on analytical size exclusion chromatography coupled with liquid chromatography-tandem mass spectrometry. Application of this screening method to the NP library led to the discovery of a potent inhibitor of TNF-α, sennoside B, with an IC₅₀ value of 0.32 µM in TNF-α induced HeLa cell toxicity assays. Surprisingly, the potency of sennoside B was 5.7-fold higher than that of the synthetic TNF-α inhibitor SPD304. Molecular docking was performed to determine the binding mode of sennoside B to TNF-α. In conclusion, we successfully developed a novel competition binding screening method to discover small molecule TNF-α inhibitors and identified the natural compound sennoside B as having exceptional potency. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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23 pages, 4873 KiB

Open AccessArticle

Identification of CDK7 Inhibitors from Natural Sources Using Pharmacoinformatics and Molecular Dynamics Simulations

by Vikas Kumar, Shraddha Parate, Gunjan Thakur, Gihwan Lee, Hyeon-Su Ro, Yongseong Kim, Hong Ja Kim, Myeong Ok Kim and Keun Woo Lee

Biomedicines 2021, 9(9), 1197; https://doi.org/10.3390/biomedicines9091197 - 10 Sep 2021

Cited by 18 | Viewed by 4702

Abstract

The cyclin-dependent kinase 7 (CDK7) plays a crucial role in regulating the cell cycle and RNA polymerase-based transcription. Overexpression of this kinase is linked with various cancers in humans due to its dual involvement in cell development. Furthermore, emerging evidence has revealed that [...] Read more.

The cyclin-dependent kinase 7 (CDK7) plays a crucial role in regulating the cell cycle and RNA polymerase-based transcription. Overexpression of this kinase is linked with various cancers in humans due to its dual involvement in cell development. Furthermore, emerging evidence has revealed that inhibiting CDK7 has anti-cancer effects, driving the development of novel and more cost-effective inhibitors with enhanced selectivity for CDK7 over other CDKs. In the present investigation, a pharmacophore-based approach was utilized to identify potential hit compounds against CDK7. The generated pharmacophore models were validated and used as 3D queries to screen 55,578 natural drug-like compounds. The obtained compounds were then subjected to molecular docking and molecular dynamics simulations to predict their binding mode with CDK7. The molecular dynamics simulation trajectories were subsequently used to calculate binding affinity, revealing four hits—ZINC20392430, SN00112175, SN00004718, and SN00262261—having a better binding affinity towards CDK7 than the reference inhibitors (CT7001 and THZ1). The binding mode analysis displayed hydrogen bond interactions with the hinge region residues Met94 and Glu95, DFG motif residue Asp155, ATP-binding site residues Thr96, Asp97, and Gln141, and quintessential residue outside the kinase domain, Cys312 of CDK7. The in silico selectivity of the hits was further checked by docking with CDK2, the close homolog structure of CDK7. Additionally, the detailed pharmacokinetic properties were predicted, revealing that our hits have better properties than established CDK7 inhibitors CT7001 and THZ1. Hence, we argue that proposed hits may be crucial against CDK7-related malignancies. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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14 pages, 3521 KiB

Open AccessArticle

The Azurin-Derived Peptide CT-p19LC Exhibits Membrane-Active Properties and Induces Cancer Cell Death

by Ana Rita Garizo, Lígia F. Coelho, Sandra Pinto, Tiago P. Dias, Fábio Fernandes, Nuno Bernardes and Arsénio M. Fialho

Biomedicines 2021, 9(9), 1194; https://doi.org/10.3390/biomedicines9091194 - 10 Sep 2021

Cited by 9 | Viewed by 3561

Abstract

Peptides have been thoroughly studied as new therapeutic strategies for cancer treatment. In this work, we explored in vitro the anticancer potential of three novel peptides derived from the C-terminal of azurin, an anticancer bacterial protein produced by Pseudomonas aeruginosa. CT-p26, CT-p19 [...] Read more.

Peptides have been thoroughly studied as new therapeutic strategies for cancer treatment. In this work, we explored in vitro the anticancer potential of three novel peptides derived from the C-terminal of azurin, an anticancer bacterial protein produced by Pseudomonas aeruginosa. CT-p26, CT-p19 and CT-p19LC peptides were previously obtained through an in silico peptide design optimization process, CT-p19LC being the most promising as it presented higher hydrophobicity and solubility, positive total charge and, most importantly, greater propensity for anticancer activity. Therefore, in this study, through proliferation and apoptosis assays, CT-p19LC was tested in four cancer cell lines—A549, MCF-7, HeLa and HT-29—and in two non-cancer cell lines—16HBE14o- and MCF10A. Its membrane-targeting activity was further evaluated with zeta potential measurements and membrane order was assessed with the Laurdan probe. The results obtained demonstrated that CT-p19LC decreases cell viability through induction of cell death and binds to the plasma membrane of cancer cells, but not to non-cancer cells, making them less rigid. Overall, this study reveals that CT-p19LC is an auspicious selective anticancer peptide able to react with cancer cell membranes and cause effective action. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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18 pages, 5381 KiB

Open AccessArticle

Effective Accentuation of Voltage-Gated Sodium Current Caused by Apocynin (4′-Hydroxy-3′-methoxyacetophenone), a Known NADPH-Oxidase Inhibitor

by Tzu-Hsien Chuang, Hsin-Yen Cho and Sheng-Nan Wu

Biomedicines 2021, 9(9), 1146; https://doi.org/10.3390/biomedicines9091146 - 3 Sep 2021

Cited by 9 | Viewed by 2255

Abstract

Apocynin (aPO, 4′-Hydroxy-3′-methoxyacetophenone) is a cell-permeable, anti-inflammatory phenolic compound that acts as an inhibitor of NADPH-dependent oxidase (NOX). However, the mechanisms through which aPO can interact directly with plasmalemmal ionic channels to perturb the amplitude or gating of ionic currents in [...] Read more.

Apocynin (aPO, 4′-Hydroxy-3′-methoxyacetophenone) is a cell-permeable, anti-inflammatory phenolic compound that acts as an inhibitor of NADPH-dependent oxidase (NOX). However, the mechanisms through which aPO can interact directly with plasmalemmal ionic channels to perturb the amplitude or gating of ionic currents in excitable cells remain incompletely understood. Herein, we aimed to investigate any modifications of aPO on ionic currents in pituitary GH₃ cells or murine HL-1 cardiomyocytes. In whole-cell current recordings, GH₃-cell exposure to aPO effectively stimulated the peak and late components of voltage-gated Na+ current (I_Na) with different potencies. The EC₅₀ value of aPO required for its differential increase in peak or late I_Na in GH₃ cells was estimated to be 13.2 or 2.8 μM, respectively, whereas the K_D value required for its retardation in the slow component of current inactivation was 3.4 μM. The current–voltage relation of I_Na was shifted slightly to more negative potential during cell exposure to aPO (10 μM); however, the steady-state inactivation curve of the current was shifted in a rightward direction in its presence. Recovery of peak I_Na inactivation was increased in the presence of 10 μM aPO. In continued presence of aPO, further application of rufinamide or ranolazine attenuated aPO-stimulated I_Na. In methylglyoxal- or superoxide dismutase-treated cells, the stimulatory effect of aPO on peak I_Na remained effective. By using upright isosceles-triangular ramp pulse of varying duration, the amplitude of persistent I_Na measured at low or high threshold was enhanced by the aPO presence, along with increased hysteretic strength appearing at low or high threshold. The addition of aPO (10 μM) mildly inhibited the amplitude of erg-mediated K+ current. Likewise, in HL-1 murine cardiomyocytes, the aPO presence increased the peak amplitude of I_Na as well as decreased the inactivation or deactivation rate of the current, and further addition of ranolazine or esaxerenone attenuated aPO-accentuated I_Na. Altogether, this study provides a distinctive yet unidentified finding that, despite its effectiveness in suppressing NOX activity, aPO may directly and concertedly perturb the amplitude, gating and voltage-dependent hysteresis of I_Na in electrically excitable cells. The interaction of aPO with ionic currents may, at least in part, contribute to the underlying mechanisms through which it affects neuroendocrine, endocrine or cardiac function. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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20 pages, 3852 KiB

Open AccessArticle

Development of New Meridianin/Leucettine-Derived Hybrid Small Molecules as Nanomolar Multi-Kinase Inhibitors with Antitumor Activity

by Mohamed H. Elsherbeny, Ahmed Elkamhawy, Hossam Nada, Magda H. Abdellattif, Kyeong Lee and Eun Joo Roh

Biomedicines 2021, 9(9), 1131; https://doi.org/10.3390/biomedicines9091131 - 1 Sep 2021

Cited by 9 | Viewed by 3119

Abstract

Although the sea ecosystem offers a broad range of bioactivities including anticancer, none of the FDA-approved antiproliferative protein kinase inhibitors are derived from a marine source. In a step to develop new marine-inspired potent kinase inhibitors with antiproliferative activities, a new series of [...] Read more.

Although the sea ecosystem offers a broad range of bioactivities including anticancer, none of the FDA-approved antiproliferative protein kinase inhibitors are derived from a marine source. In a step to develop new marine-inspired potent kinase inhibitors with antiproliferative activities, a new series of hybrid small molecules (5a–5g) was designed and synthesized based on chemical moieties derived from two marine natural products (Meridianin E and Leucettamine B). Over a panel of 14 cancer-related kinases, a single dose of 10 µM of the parent hybrid 5a possessing the benzo[d][1,3]dioxole moiety of Leucettamine B was able to inhibit the activity of FMS, LCK, LYN, and DAPK1 kinases with 82.5 ± 0.6, 81.4 ± 0.6, 75.2 ± 0.0, and 55 ± 1.1%, respectively. Further optimization revealed the most potent multiple kinase inhibitor of this new series (5g) with IC₅₀ values of 110, 87.7, and 169 nM against FMS, LCK, and LYN kinases, respectively. Compared to imatinib (FDA-approved multiple kinase inhibitor), compound 5g was found to be ~ 9- and 2-fold more potent than imatinib over both FMS and LCK kinases, respectively. In silico docking simulation models of the synthesized compounds within the active site of FMS, LCK, LYN, and DAPK1 kinases offered reasonable explanations of the elicited biological activities. In an in vitro anticancer assay using a library of 60 cancer cell lines that include blood, lung, colon, CNS, skin, ovarian, renal, prostate, and breast cancers, it was found that compound 5g was able to suppress 60 and 70% of tumor growth in leukemia SR and renal RXF 393 cell lines, respectively. Moreover, an ADME study indicated a suitable profile of compound 5g concerning cell permeability and blood-brain barrier (BBB) impermeability, avoiding possible CNS side effects. Accordingly, compound 5g is reported as a potential lead towards novel antiproliferative marine-derived kinase modulators. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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25 pages, 4898 KiB

Open AccessArticle

Hexapod Assassins’ Potion: Venom Composition and Bioactivity from the Eurasian Assassin Bug Rhynocoris iracundus

by Nicolai Rügen, Timothy P. Jenkins, Natalie Wielsch, Heiko Vogel, Benjamin-Florian Hempel, Roderich D. Süssmuth, Stuart Ainsworth, Alejandro Cabezas-Cruz, Andreas Vilcinskas and Miray Tonk

Biomedicines 2021, 9(7), 819; https://doi.org/10.3390/biomedicines9070819 - 14 Jul 2021

Cited by 9 | Viewed by 5652

Abstract

Assassin bug venoms are potent and exert diverse biological functions, making them potential biomedical goldmines. Besides feeding functions on arthropods, assassin bugs also use their venom for defense purposes causing localized and systemic reactions in vertebrates. However, assassin bug venoms remain poorly characterized. [...] Read more.

Assassin bug venoms are potent and exert diverse biological functions, making them potential biomedical goldmines. Besides feeding functions on arthropods, assassin bugs also use their venom for defense purposes causing localized and systemic reactions in vertebrates. However, assassin bug venoms remain poorly characterized. We collected the venom from the assassin bug Rhynocoris iracundus and investigated its composition and bioactivity in vitro and in vivo. It caused lysis of murine neuroblastoma, hepatoma cells, and healthy murine myoblasts. We demonstrated, for the first time, that assassin bug venom induces neurolysis and suggest that it counteracts paralysis locally via the destruction of neural networks, contributing to tissue digestion. Furthermore, the venom caused paralysis and melanization of Galleria mellonella larvae and pupae, whilst also possessing specific antibacterial activity against Escherichia coli, but not Listeria grayi and Pseudomonas aeruginosa. A combinatorial proteo-transcriptomic approach was performed to identify potential toxins responsible for the observed effects. We identified neurotoxic Ptu1, an inhibitory cystin knot (ICK) toxin homologous to ω-conotoxins from cone snails, cytolytic redulysins homologous to trialysins from hematophagous kissing bugs, and pore-forming hemolysins. Additionally, chitinases and kininogens were found and may be responsible for insecticidal and cytolytic activities. We demonstrate the multifunctionality and complexity of assassin bug venom, which renders its molecular components interesting for potential biomedical applications. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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12 pages, 5051 KiB

Open AccessArticle

Generation of Stilbene Glycoside with Promising Cell Rejuvenation Activity through Biotransformation by the Entomopathogenic Fungus Beauveria bassiana

by Sang Keun Ha, Min Cheol Kang, Seulah Lee, Om Darlami, Dongyun Shin, Inwook Choi, Ki Hyun Kim and Sun Yeou Kim

Biomedicines 2021, 9(5), 555; https://doi.org/10.3390/biomedicines9050555 - 17 May 2021

Cited by 5 | Viewed by 3020

Abstract

A stilbene glycoside (resvebassianol A) (1) with a unique sugar unit, 4-O-methyl-D-glucopyranose, was identified through biotransformation of resveratrol (RSV) by the entomopathogenic fungus Beauveria bassiana to obtain a superior RSV metabolite with enhanced safety. Its structure, including its absolute [...] Read more.

A stilbene glycoside (resvebassianol A) (1) with a unique sugar unit, 4-O-methyl-D-glucopyranose, was identified through biotransformation of resveratrol (RSV) by the entomopathogenic fungus Beauveria bassiana to obtain a superior RSV metabolite with enhanced safety. Its structure, including its absolute configurations, was determined using spectroscopic data, HRESIMS, and chemical reactions. Microarray analysis showed that the expression levels of filaggrin, HAS2-AS1, and CERS3 were higher, while those of IL23A, IL1A, and CXCL8 were lower in the resvebassianol A-treated group than in the RSV-treated group, as confirmed by qRT-PCR. Compound 1 exhibited the same regenerative and anti-inflammatory effects as RSV with no cytotoxicity in skin keratinocytes and TNF-α/IFN-γ-stimulated HIEC-6 cells, suggesting that compound 1 is a safe and stable methylglycosylated RSV. Our findings suggest that our biotransformation method can be an efficient biosynthetic platform for producing a broad range of natural glycosides with enhanced safety. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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17 pages, 4284 KiB

Open AccessArticle

N-Alkylation of Anthracycline Antibiotics by Natural Sesquiterpene Lactones as a Way to Obtain Antitumor Agents with Reduced Side Effects

by Margarita Neganova, Alexey Semakov, Yulia Aleksandrova, Ekaterina Yandulova, Sergey Pukhov, Lada Anikina and Sergey Klochkov

Biomedicines 2021, 9(5), 547; https://doi.org/10.3390/biomedicines9050547 - 13 May 2021

Cited by 15 | Viewed by 3438

Abstract

Anthracycline antitumor antibiotics are one of the promising classes of chemotherapeutic agents for cancer treatment. The main deterrent to their use is high toxicity to a healthy environment, including cumulative cardiotoxicity. In our work, bipharmacophore molecules containing in their structure a fragment of [...] Read more.

Anthracycline antitumor antibiotics are one of the promising classes of chemotherapeutic agents for cancer treatment. The main deterrent to their use is high toxicity to a healthy environment, including cumulative cardiotoxicity. In our work, bipharmacophore molecules containing in their structure a fragment of the known anthracycline antibiotics daunorubicin and doxorubicin and natural sesquiterpene lactones were obtained for the first time. When studying the biological activity of the synthesized compounds, it was found that with equal and, in some cases, higher cytotoxicity and glycolysis inhibition by anthracycline antibiotics conjugates with sesquiterpene lactones in comparison with doxo- and daunorubicin, a reduced damaging effect on the functioning of rat heart mitochondria was observed. The results obtained allow us to confirm the assumption that the chemical modification of the anthracycline antibiotics molecules doxo- and daunorubicin by natural sesquiterpene lactones can be a promising strategy for creating potential antitumor chemotherapeutic drugs with a pronounced cytotoxic effect on tumor cells and a reduced damaging effect on healthy cells of the human organism. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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20 pages, 5477 KiB

Open AccessArticle

Optimized Synthesis of New N-Mustards Based on 2-Mercaptobenzoxazole Derivatives with Antitumor Activity

by Corina Cheptea, Valeriu Sunel, Ana Cezarina Morosanu, Dan Gheorghe Dimitriu, Mihaela Maria Dulcescu-Oprea, Mihai-Daniel Angheluta, Mihaela Miron, Cristina Delia Nechifor, Dana Ortansa Dorohoi and Razvan Nicolae Malancus

Biomedicines 2021, 9(5), 476; https://doi.org/10.3390/biomedicines9050476 - 26 Apr 2021

Cited by 4 | Viewed by 2875

Abstract

New di-(β-chloroethyl)-amides of some acids derived from 2-mercaptobenzoxazole were prepared by reaction of the corresponding pivalic mixed anhydrides with di-(β-chloroethyl)-amine. A study regarding the optimization of the chemical reactions was made for the case of di-(β-chloroethyl)-amines. The quantum chemical analysis by Spartan’14 was [...] Read more.

New di-(β-chloroethyl)-amides of some acids derived from 2-mercaptobenzoxazole were prepared by reaction of the corresponding pivalic mixed anhydrides with di-(β-chloroethyl)-amine. A study regarding the optimization of the chemical reactions was made for the case of di-(β-chloroethyl)-amines. The quantum chemical analysis by Spartan’14 was made in order to establish the most stable configuration of the ground electronic states for the obtained chemical structures and some physico-chemical parameters of N-mustards reported in this paper. Mercaptobenzoxazoles substituted in the side chain with the cytotoxic group show antitumor activity and they inhibit Ehrlich Ascites in an appreciable proportion compared to the drug I.O.B.-82, as our studies evidenced. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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20 pages, 4065 KiB

Open AccessArticle

Ferulic Acid Induces Keratin 6α via Inhibition of Nuclear β-Catenin Accumulation and Activation of Nrf2 in Wound-Induced Inflammation

by Kang-Hoon Kim, Ji Hoon Jung, Won-Seok Chung, Chang-Hun Lee and Hyeung-Jin Jang

Biomedicines 2021, 9(5), 459; https://doi.org/10.3390/biomedicines9050459 - 22 Apr 2021

Cited by 11 | Viewed by 3236

Abstract

Injured tissue triggers complex interactions through biological process associated with keratins. Rapid recovery is most important for protection against secondary infection and inflammatory pain. For rapid wound healing with minimal pain and side effects, shilajit has been used as an ayurvedic medicine. However, [...] Read more.

Injured tissue triggers complex interactions through biological process associated with keratins. Rapid recovery is most important for protection against secondary infection and inflammatory pain. For rapid wound healing with minimal pain and side effects, shilajit has been used as an ayurvedic medicine. However, the mechanisms of rapid wound closure are unknown. Here, we found that shilajit induced wound closure in an acute wound model and induced migration in skin explant cultures through evaluation of transcriptomics via microarray testing. In addition, ferulic acid (FA), as a bioactive compound, induced migration via modulation of keratin 6α (K6α) and inhibition of β-catenin in primary keratinocytes of skin explant culture and injured full-thickness skin, because accumulation of β-catenin into the nucleus acts as a negative regulator and disturbs migration in human epidermal keratinocytes. Furthermore, FA alleviated wound-induced inflammation via activation of nuclear factor erythroid-2-related factor 2 (Nrf2) at the wound edge. These findings show that FA is a novel therapeutic agent for wound healing that acts via inhibition of β-catenin in keratinocytes and by activation of Nrf2 in wound-induced inflammation. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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20 pages, 2667 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Rutin Is a Low Micromolar Inhibitor of SARS-CoV-2 Main Protease 3CLpro: Implications for Drug Design of Quercetin Analogs

by Bruno Rizzuti, Fedora Grande, Filomena Conforti, Ana Jimenez-Alesanco, Laura Ceballos-Laita, David Ortega-Alarcon, Sonia Vega, Hugh T. Reyburn, Olga Abian and Adrian Velazquez-Campoy

Biomedicines 2021, 9(4), 375; https://doi.org/10.3390/biomedicines9040375 - 2 Apr 2021

Cited by 61 | Viewed by 5510

Abstract

The pandemic, due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has stimulated the search for antivirals to tackle COVID-19 infection. Molecules with known pharmacokinetics and already approved for human use have been demonstrated or predicted to be suitable to be used either [...] Read more.

The pandemic, due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has stimulated the search for antivirals to tackle COVID-19 infection. Molecules with known pharmacokinetics and already approved for human use have been demonstrated or predicted to be suitable to be used either directly or as a base for a scaffold-based drug design. Among these substances, quercetin is known to be a potent in vitro inhibitor of 3CLpro, the SARS-CoV-2 main protease. However, its low in vivo bioavailability calls for modifications to its molecular structure. In this work, this issue is addressed by using rutin, a natural flavonoid that is the most common glycosylated conjugate of quercetin, as a model. Combining experimental (spectroscopy and calorimetry) and simulation techniques (docking and molecular dynamics simulations), we demonstrate that the sugar adduct does not hamper rutin binding to 3CLpro, and the conjugated compound preserves a high potency (inhibition constant in the low micromolar range, K_i = 11 μM). Although showing a disruption of the pseudo-symmetry in the chemical structure, a larger steric volume and molecular weight, and a higher solubility compared to quercetin, rutin is able to associate in the active site of 3CLpro, interacting with the catalytic dyad (His41/Cys145). The overall results have implications in the drug-design of quercetin analogs, and possibly other antivirals, to target the catalytic site of the SARS-CoV-2 3CLpro. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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17 pages, 2497 KiB

Open AccessArticle

Discovery through Machine Learning and Preclinical Validation of Novel Anti-Diabetic Peptides

by Rory Casey, Alessandro Adelfio, Martin Connolly, Audrey Wall, Ian Holyer and Nora Khaldi

Biomedicines 2021, 9(3), 276; https://doi.org/10.3390/biomedicines9030276 - 9 Mar 2021

Cited by 17 | Viewed by 4815

Abstract

While there have been significant advances in drug discovery for diabetes mellitus over the past couple of decades, there is an opportunity and need for improved therapies. While type 2 diabetic patients better manage their illness, many of the therapeutics in this area [...] Read more.

While there have been significant advances in drug discovery for diabetes mellitus over the past couple of decades, there is an opportunity and need for improved therapies. While type 2 diabetic patients better manage their illness, many of the therapeutics in this area are peptide hormones with lengthy sequences and a molecular structure that makes them challenging and expensive to produce. Using machine learning, we present novel anti-diabetic peptides which are less than 16 amino acids in length, distinct from human signalling peptides. We validate the capacity of these peptides to stimulate glucose uptake and Glucose transporter type 4 (GLUT4) translocation in vitro. In obese insulin-resistant mice, predicted peptides significantly lower plasma glucose, reduce glycated haemoglobin and even improve hepatic steatosis when compared to treatments currently in use in a clinical setting. These unoptimised, linear peptides represent promising candidates for blood glucose regulation which require further evaluation. Further, this indicates that perhaps we have overlooked the class of natural short linear peptides, which usually come with an excellent safety profile, as therapeutic modalities. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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12 pages, 2701 KiB

Open AccessArticle

Anti-Adipogenic Polyacetylene Glycosides from the Florets of Safflower (Carthamus tinctorius)

by Su Cheol Baek, Sang Ah Yi, Bum Soo Lee, Jae Sik Yu, Jin-Chul Kim, Changhyun Pang, Tae Su Jang, Jaecheol Lee and Ki Hyun Kim

Biomedicines 2021, 9(1), 91; https://doi.org/10.3390/biomedicines9010091 - 19 Jan 2021

Cited by 12 | Viewed by 3720

Abstract

Safflower (Carthamus tinctorius) is an annual herb belonging to the Compositae family; it has a history of use as a food colorant, dye, and medicine in oriental countries. LC-MS-UV-based chemical analysis of extract of the florets of C. tinctorius led to [...] Read more.

Safflower (Carthamus tinctorius) is an annual herb belonging to the Compositae family; it has a history of use as a food colorant, dye, and medicine in oriental countries. LC-MS-UV-based chemical analysis of extract of the florets of C. tinctorius led to the isolation of two new C₁₀-polyacetylene glycosides, (8Z)-decaene-4,6-diyne-1,10-diol-1-O-β-d-glucopyranoside (1) and (8S)-deca-4,6-diyne-1,8-diol-1-O-β-d-glucopyranoside (2), together with five known analogs (3–7). The structures of the new compounds were determined by using 1D and 2D NMR spectroscopic data and HR-MS data, as well as chemical transformations. Of compounds 1–7, compounds 2, 3, and 4 inhibited the adipogenesis of 3T3-L1 preadipocytes, whereas compounds 1 and 6 promoted adipogenesis. Compounds 2, 3, and 4 also prevented lipid accumulation through the suppression of the expression of lipogenic genes and the increase of the expression of lipolytic genes. Moreover, compounds 3 and 4 activated AMPK, which is known to facilitate lipid metabolism. Our findings provide a mechanistic rationale for the use of safflower-derived polyacetylene glycosides as potential therapeutic agents against obesity. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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10 pages, 1849 KiB

Open AccessArticle

Molecular Docking Simulations on Histone Deacetylases (HDAC)-1 and -2 to Investigate the Flavone Binding

by Bernardina Scafuri, Paola Bontempo, Lucia Altucci, Luigi De Masi and Angelo Facchiano

Biomedicines 2020, 8(12), 568; https://doi.org/10.3390/biomedicines8120568 - 4 Dec 2020

Cited by 33 | Viewed by 4758

Abstract

Histone modifications through acetylation are fundamental for remodelling chromatin and consequently activating gene expression. The imbalance between acetylation and deacetylation activity causes transcriptional dysregulation associated with several disorders. Flavones, small molecules of plant origin, are known to interfere with class I histone deacetylase [...] Read more.

Histone modifications through acetylation are fundamental for remodelling chromatin and consequently activating gene expression. The imbalance between acetylation and deacetylation activity causes transcriptional dysregulation associated with several disorders. Flavones, small molecules of plant origin, are known to interfere with class I histone deacetylase (HDAC) enzymes and to enhance acetylation, restoring cell homeostasis. To investigate the possible physical interactions of flavones on human HDAC1 and 2, we carried out in silico molecular docking simulations. Our data have revealed how flavone, and other two flavones previously investigated, i.e., apigenin and luteolin, can interact as ligands with HDAC1 and 2 at the active site binding pocket. Regulation of HDAC activity by dietary flavones could have important implications in developing epigenetic therapy to regulate the cell gene expression. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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Review

Jump to: Editorial, Research

25 pages, 10920 KiB

Open AccessReview

Recent Advances in Improved Anticancer Efficacies of Camptothecin Nano-Formulations: A Systematic Review

by Maryam Ghanbari-Movahed, Tea Kaceli, Arijit Mondal, Mohammad Hosein Farzaei and Anupam Bishayee

Biomedicines 2021, 9(5), 480; https://doi.org/10.3390/biomedicines9050480 - 27 Apr 2021

Cited by 53 | Viewed by 6182

Abstract

Camptothecin (CPT), a natural plant alkaloid, has indicated potent antitumor activities via targeting intracellular topoisomerase I. The promise that CPT holds in therapies is restricted through factors that include lactone ring instability and water insolubility, which limits the drug oral solubility and bioavailability [...] Read more.

Camptothecin (CPT), a natural plant alkaloid, has indicated potent antitumor activities via targeting intracellular topoisomerase I. The promise that CPT holds in therapies is restricted through factors that include lactone ring instability and water insolubility, which limits the drug oral solubility and bioavailability in blood plasma. Novel strategies involving CPT pharmacological and low doses combined with nanoparticles have indicated potent anticancer activity in vitro and in vivo. This systematic review aims to provide a comprehensive and critical evaluation of the anticancer ability of nano-CPT in various cancers as a novel and more efficient natural compound for drug development. Studies were identified through systematic searches of PubMed, Scopus, and ScienceDirect. Eligibility checks were performed based on predefined selection criteria. Eighty-two papers were included in this systematic review. There was strong evidence for the association between antitumor activity and CPT treatment. Furthermore, studies indicated that CPT nano-formulations have higher antitumor activity in comparison to free CPT, which results in enhanced efficacy for cancer treatment. The results of our study indicate that CPT nano-formulations are a potent candidate for cancer treatment and may provide further support for the clinical application of natural antitumor agents with passive targeting of tumors in the future. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery of Novel Drugs on Natural Molecules)

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