Natural Products and Bioprospecting最新文献

Qingfei Paidu decoction (QFPDD) has been extensively used in clinical treatments during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic. SARS-CoV-2 primarily invades host cells via its spike (S) protein binding to the angiotensin-converting enzyme 2 (ACE2) on the cell membrane, mediating viral-host membrane fusion. Blocking viral entry is a crucial step in preventing infection, with the interaction between the S receptor binding domain (S-RBD) and ACE2 being a key antiviral target. Given that SARS-CoV-2 predominantly affects the respiratory system and approximately 25% of patients suffering from corona virus disease 2019 (COVID-19) with gastrointestinal symptoms, we are committed to identifying more active ingredients in QFPDD that target the respiratory and gastrointestinal tracts of COVID-19 patients. Among medicinal plants, ephedra and liquorice derived from QFPDD, along with two other Chinese herbs, Platycodon grandiflorum and Radix Rhei Et Rhizome (rhubarb), have garnered our interest. These herbs have historically been used in traditional Chinese medicine (TCM) for treating infectious diseases with respiratory and digestive symptoms. Here, we established a library containing all components of the four individual herbs gathered from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and performed structure-based virtual screening to identify potential ACE2/S-RBD inhibitors. Subsequently, we selected 10 ingredients from the top 30 candidates and evaluated their activities using a pseudovirus neutralization assay. Delphinidin and deapio platycodin D (DPD) showed significant antiviral potential with half-maximal inhibitory concentration (IC₅₀) values of 45.35 µM and 1.38 µM, respectively. Furthermore, delphinidin also inhibited the 3-chymotrypsin-like protease (3CL^pro), indicating its dual-viral target inhibitory potential. Notably, DPD effectively suppressed HCoV-229E replication in BEL-7402 cells. This study not only provides a strategy for rapid identifying antiviral agents from TCM in anticipation of future pandemics but also offers theoretical and experimental evidence to support for the clinical use of QFPDD.

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The activation of conventional (α) and novel (δ) protein kinase C (PKC) isoforms promotes lysosomal biogenesis, a critical process for clearance of pathogenic protein aggregates including β-amyloid (Aβ) and phosphorylated Tau (p-Tau) in neurodegenerative disorders. Notably, PKC activators HEP14/15, characterized by 20-methyl moiety, fail to establish classical C1B domain pharmacophore interactions, suggesting a non-canonical activation mechanism. In this study, structural diversification of 20-deoxyingenol through esterification and acetonide protection yielded 18 new derivatives (2–19). Systematic screening revealed their lysosome-promoting activities, with structure–activity relationship analysis identifying compounds 4 and 18 as superior autophagy inducers. At 20 μM, these derivatives enhanced autophagic flux by 2.45-fold and 2.31-fold versus vehicle control. Moreover, compounds 4 and 18 exhibited a dose-dependent increase in lysosome numbers, promoted TFEB nuclear translocation, and enhanced lysosome-mediated lipid droplet clearance. Western blot analysis further revealed that compounds 4/18 upregulated proteins associated with the autophagy-lysosome system, suggesting their potential as promising autophagy inducers. Mechanistically, molecular docking simulations indicated thier high-affinity binding to PKCδ, which may explain their autophagy-enhancing properties.

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Natural products (NPs) are invaluable resources for drug discovery, characterized by their intricate scaffolds and diverse bioactivities. AI drug discovery & design (AIDD) has emerged as a transformative approach for the rational structural modification of NPs. This review examines a variety of molecular generation models since 2020, focusing on their potential applications in two primary scenarios of NPs structure modification: modifications when the target is identified and when it remains unidentified. Most of the molecular generative models discussed herein are open-source, and their applicability across different domains and technical feasibility have been evaluated. This evaluation was accomplished by integrating a limited number of research cases and successful practices observed in the molecular optimization of synthetic compounds. Furthermore, the challenges and prospects of employing molecular generation modeling for the structural modification of NPs are discussed.

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The use of natural products as antibiotic adjuvants to enhance efficacy and mitigate resistance is increasingly recognized as a promising strategy. This study explored five novel synergistic antimicrobial combinations (SACs) of carvacrol (CARV) and three already identified SACs of thymol (THY) with chloramphenicol, gentamicin, and streptomycin against Staphylococcus aureus and Acinetobacter baumannii, critical WHO-listed pathogens, and investigated their mechanisms of action and resistance-prevention capabilities. Despite being isomers, CARV and THY exhibited distinct synergistic effects and fractional inhibitory concentration index (FICI) values depending on the antibiotic and bacterial species. The SACs significantly reduced the required antibiotic dose by 4- to 16-fold, with FICI values ranging from 0.25 to 0.5. Growth kinetics revealed that SACs completely inhibited planktonic bacterial growth, outperforming antibiotics alone. Additionally, the SACs demonstrated efficacy in both inhibiting and eradicating biofilms of S. aureus and A. baumannii. Resistance development studies highlighted that neither THY nor CARV induced resistance in these pathogens. Moreover, SACs combining aminoglycosides with THY reduced the emergence of resistance in A. baumannii by up to 32-fold. In S. aureus, THY mitigated gentamicin resistance by 16-fold. CARV exhibited similar, albeit slightly less potent, effects.

Mechanistic investigations revealed that THY and CARV exert antimicrobial action by multiple mechanisms, including bacterial membrane depolarization and disruption, efflux pump inhibition, disrupting ATP metabolism and mitigating oxidative stress induced by antibiotics. These findings highlight the potential of SACs to enhance antibiotic efficacy while preventing resistance, positioning them as strong candidates for innovative antimicrobial therapies against multidrug-resistant pathogens.

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Two new together with 32 known compounds were isolated from the leaves of Lycium barbarum. Their structures were elucidated using 1D and 2D NMR, HRESIMS, and ECD spectroscopic techniques. Compounds 1–34 were evaluated for their anti-rheumatoid arthritis activities in a lipopolysaccharide (LPS)-induced MH7A cells inflammatory model. As a result, compounds 1–3, 6, 8, 10, 14, 17–19, 29 and 31 inhibited the activity of lactate dehydrogenase (LDH) and nitric oxide (NO) at concentrations 20 μM. Among them, compound 1 showed the best effectiveness, with inhibition rates of 46.7% for NO and 32.8% for LDH.

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Our continuous study of the fruits of Garcinia xanthochymus and Garcinia subelliptica led to the isolation and structural characterization of six new polyprenylated acylphloroglucinols, xanthochymusones N and O (1 and 2), (–)-garciyunnanin L (3), and garsubelones C–E (4–6), together with two known analogues. Their structures were elucidated by interpretation of NMR and MS spectroscopic data. It was found that the Grossman-Jacobs rule is no longer applicable to determination of the C-7 configuration of compounds 1–3, as they possess a complex 6/6/6/6/6 fused ring system. The inhibitory activities of all the compounds against two human hepatocellular carcinoma cell lines Huh-7 and HepG2 were evaluated, and compound 1 exhibited moderate cytotoxic activities against HepG2 cells with IC₅₀ value 7.3 μM. Furthermore, the previous assignments of some polyprenylated acylphloroglucinols have been proved to be incorrect in this study, and analysis of NMR data enabled the structural revision of seven analogues: hyperselancins A and B, garcinielliptones F and G, garxanthochins A and B, and 13,14-didehydroxygarcicowin C. The revised structures of garcinielliptone F and garxanthochin A were shown to have the same structures of garsubelone B and xanthochymusone K, respectively, and the revised structures of other five compounds have not been reported.

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Otteacumienes G–K (1–5), five pairs of enantiomeric diarylheptanoids, along with one undescribed diarylheptanoid glycoside and one new lignan, were isolated from Ottelia acuminata var. acuminata. Compounds 1–5 were identified as five pairs of enantiomers and their structural configurations were determined through a combination of spectroscopic analysis, X-ray crystallography, and ECD calculation. Notably, compound 6 was the first diarylheptanoid glycoside isolated from this aquatic species, and its absolute configuration was unequivocally established through semi-synthesis. Biological evaluation demonstrated that compound 1 exhibited α-glucosidase inhibitory activity, with an inhibition ratio of 38.97% (acarbose as the positive control, inhibition ratio = 13.52%).

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Two concise and efficient synthetic routes were developed for the synthesis of three 1,7-diarylheptanoids (1–3) containing a 1,4-pentadiene unit, which were originally isolated from Ottelia acuminata var. acuminata. The first approach focused on the construction of linear diarylheptanoids 1 and 3 featuring a (1E,4E)-pentadiene moiety, via a Suzuki coupling reaction. The second strategy enabled the synthesis of sixteen-membered macrocyclic ether 2 with a (1Z,4E)-pentadiene unit. The challenging macrocyclization was successfully accomplished through an Ullmann coupling. Notably, the formation of the Z-olefin within the macrocyclic framework was promoted by the inherent ring strain of diarylether-type heptane system, which preferentially stabilizes this particular configuration.

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In this work, six pairs of undescribed enantiomeric prenylated flavonoids, ( ±)-epimesatines J–O (1a/1b–6a/6b), were isolated from the aerial parts of Epimedium sagittatum Maxim. Their structures and absolute configurations were determined based on spectroscopic data, quantum chemical calculations of electronic circular dichroism (ECD) and ¹³C NMR, as well as ECD experiments induced by Mo₂(OAc)₄ and Rh₂(OCOCF₃)₄. The cytotoxicity assay revealed that compounds 1a/1b, 2a/2b, and 4a/4b–6a/6b demonstrated significant inhibitory effects on the viability of human breast cancer cells MCF-7 while exhibiting no obvious toxicity towards human breast epithelial cells MCF-10A. Additionally, these compounds were found to decrease the expression of sphingosine kinase 1 (Sphk1) in MCF-7 cells. Notably, compounds 4a and 5b exhibited IC₅₀ values of 7.45 and 8.97 μM, respectively, in MCF-7 cells.

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Pseudomonas aeruginosa-induced bacterial keratitis is one of the most sight-threatening corneal infections associated with intense ocular inflammatory reactions that may lead to vision loss. Hence, this study investigated the efficacy of three nanocomposite chitosan-coated penetration enhancer vesicles (PEVs) to augment the ocular delivery of saponin(s), α-hederin (PEVI), hederacoside C (PEVII), or both (PEVIII) for treatment of Pseudomonas keratitis and its induced inflammatory response. The three formulations were prepared using the ethanol injection method and comprehensively characterized. In vitro, the antibacterial activity of the three formulations against P. aeruginosa was evaluated using agar well-diffusion method, pyocyanin production inhibition, and swarming and twitching motility inhibition assays. The therapeutic effect of the three formulations has been investigated in P. aeruginosa keratitis by gross lesion monitoring, determination of bacterial bioburden, biochemical markers, histopathological examination, and scoring after 7 days of topical treatment. Data revealed that PEVI, PEVII, and PEVIII nanocomposites showed particle size in the nanometer range, high entrapment efficiency, good stability, and sustained release of the saponins throughout 24 h. Among them, PEVIII exhibited notably strong in vitro antipseudomonal activity. Additionally, animals treated topically with PEVIII showed an appreciable gross lesion reduction, corneal tissue improvement, and formidable bacterial load reduction compared with untreated and gentamicin sulfate eye (GENTAWISE^®) ointment-treated groups. Moreover, PEVIII treatment showed the most significant reduction in TNF-α, NF-κB, ROS levels, and OPRL virulence gene expression while enhancing PI3K/Akt activation. Therefore, this study offers PEVIII as a promising treatment for P. aeruginosa keratitis.

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