Antimicrobial bianthrones from the crinoid sp.

Antimicrobial resistance is a global public health problem and identification of new chemical scaffolds is important to overcoming this threat. In a recent high-throughput discovery campaign, fractions derived from the organic extract of crinoid, sp. (Echinodermata), showed antibacterial activity.

New Discorhabdin D Analogues from spp. Sponges.

Chemical profiles of and were investigated, resulting in the isolation of five new discorhabdin D derivatives and -. Their planar structures were solved by combination of NMR and HR-MS, while -based configurational analysis, computational techniques, and semisynthetic methods were used for the establishment of their absolute configurations. New natural products were tested for their growth inhibitory activity against the NCI-60 human tumor cell line panel, and two compounds and showed low micromolar potency.

MoMo30 Binds to SARS-CoV-2 Spike Variants and Blocks Infection by SARS-CoV-2 Pseudovirus.

MoMo30 is an antiviral protein isolated from aqueous extracts of L. (Senegalese bitter melon). Previously, we demonstrated MoMo30's antiviral activity against HIV-1.

Structure elucidation, absolute configuration, and biological evaluation of cyclic peroxides from the sponge Plakinastrella sp.

Two cyclic peroxides, plakortides V (1) and W (2) were purified from the organic extract of the sponge Plakinastrella sp. Their planar structures were established based on extensive NMR and MS analysis and the absolute configurations of the three stereogenic centers of the 1,2-dioxane moiety were determined to be 3R,4S,6S by comparative analysis of the H NMR spectral data of the R- or S-MTPA Mosher esters. Compounds 1 and 2 exhibited potent cytotoxic activity against LOX IMVI (melanoma), UO-31 (renal), and HL-60 (TB) (leukemia) cell lines in the NCI-60 cytotoxicity assay.

Acroamine A, a 2-Amino Adenine Alkaloid from the Marine Soft Coral and Its Semisynthetic Derivatives That Inhibit cAMP-Dependent Protein Kinase A Catalytic Subunit Alpha.

A high throughput screen performed to identify catalytic inhibitors of the oncogenic fusion form of cAMP-dependent protein kinase A catalytic subunit alpha (J-PKAcα) found an individual fraction from an organic extract of the marine soft coral as active. Bioassay-guided isolation led to the identification of a 2-amino adenine alkaloid acroamine A (), the first secondary metabolite discovered from this genus and previously reported as a synthetic product. As a naturally occurring protein kinase inhibitor, to unambiguously assign its chemical structure using modern spectroscopic and spectrometric techniques, five -methylated derivatives acroamines A-A (-) were semisynthesized.

Chemoreactive 2,5-Diketopiperazines from a sp., Structure Revision of Reported Analogues and Proposed Facile Transformation Pathways.

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous cancer. Two new prenylated indole 2,5-diketopiperazine alkaloids, brevianamides E1 () and E2 (), were isolated from a fungus. Both compounds showed moderate cytotoxic activity against select MCC cell lines (i.

Isolation, Characterization, and Antiproliferative Activity of Terpenoids from the Tropical Plant .

The isolation, structure determination, and biological evaluation of constituents from the organic extract of Wahlert (Meliaceae) resulted in the isolation of 51 secondary metabolites, including 14 new terpenoids (six cycloartanes, four tirucallanes/euphanes, three limonoids, and a 7-keto sterol). Among the new compounds, is the first triterpenoid with a trioxaspiro[4.4]nonane side chain, while - are the first 17-γ-lactone tetranortriterpenoids with four oxygenated functional groups at C-1, -3, -6, and -7.

KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma.

Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1 are lacking. Here, we screen 62,643 compounds using an engineered cell line that monitors PAX3-FOXO1 transcriptional activity identifying a hitherto uncharacterized compound, P3FI-63. RNA-seq, ATAC-seq, and docking analyses implicate histone lysine demethylases (KDMs) as its targets.

Unusual Vilasinin-Class Limonoids from .

Eight vilasinin-class limonoids, including the unusually chlorinated rubescins K-M (-), the 2,3-epoxylated rubescin N (), and rubescins O-R (-), were newly isolated from . The structures of the isolated compounds were determined through spectroscopic and spectrometric analyses, as well as ECD calculations. The natural occurrence of chlorinated limonoids - was confirmed by chemical methods and HPLC analysis of a roughly fractionated portion of the plant extract.

Neopetrotaurines A-C, Isoquinoline Alkaloids with an Unprecedented Taurine Bridge from the Sponge sp.

Neopetrotaurines A-C (-), unusual alkaloids possessing two isoquinoline-derived moieties that are linked via a unique taurine bridge, were isolated from a sp. marine sponge. These new compounds have proton-deficient structural scaffolds that are difficult to unambiguously assign using only conventional 2- and 3-bond H-C and H-N heteronuclear correlation data.

Formation of Trideuteromethylated Artifacts of Pyrrole-Containing Natural Products.

Pyrrole-containing natural products form a large group of structurally diverse compounds that occur in both terrestrial and marine organisms. In the present study the formation of trideuteromethylated artifacts of pyrrole-containing natural products was investigated, focusing on the discorhabdins. Three deuterated discorhabdins, , , and , were identified to be isolation procedure artifacts caused by the presence of DMSO during NMR sample preparation and handling.

Caged Xanthones and Biphenyls Isolated from the Tropical Plant .

Four cytotoxic heptacyclic caged-xanthones [gambogefic acids B-E (-)], a cytotoxic hexacyclic caged-xanthone [garcilatelic acid ()], and four biphenyl derivatives [garcilatelibiphenyls A-D (-)] were newly isolated in a phytochemical study of a 50% MeOH/CHCl extract of (Clusiaceae). The isolated compounds were evaluated for antiproliferative activity against five human tumor cell lines including a vincristine-resistant line. The new caged-xanthones displayed potent activity with IC values from 0.

Discovery and Synthesis of a Naturally Derived Protein Kinase Inhibitor that Selectively Inhibits Distinct Classes of Serine/Threonine Kinases.

The oncogenic gene fusion results in an active kinase enzyme, J-PKAcα, that has been identified as an attractive antitumor target for fibrolamellar hepatocellular carcinoma (FLHCC). A high-throughput assay was used to identify inhibitors of J-PKAcα catalytic activity by screening the NCI Program for Natural Product Discovery (NPNPD) prefractionated natural product library. Purification of the active agent from a single fraction of an sp.

Rare Caulamidine Hexacyclic Alkaloids from the Marine Ascidian sp.

Two new caulamidines C () and D () and three isocaulamidines B, C, and D (, , and ) along with the known compound caulamidine B () were isolated from the marine ascidian sp. Their structures were elucidated by analysis of nuclear magnetic resonance (NMR) and electronic circular dichroism (ECD) data. Isocaulamidines have an altered pattern of -methyl substitution (N-15 vs N-13 in the caulamidines) with a concomitant double-bond rearrangement to provide a new C-14/N-13 imine functionality.

Irreversible Inactivation of SARS-CoV-2 by Lectin Engagement with Two Glycan Clusters on the Spike Protein.

Host cell infection by SARS-CoV-2, similar to that by HIV-1, is driven by a conformationally metastable and highly glycosylated surface entry protein complex, and infection by these viruses has been shown to be inhibited by the mannose-specific lectins cyanovirin-N (CV-N) and griffithsin (GRFT). We discovered in this study that CV-N not only inhibits SARS-CoV-2 infection but also leads to irreversibly inactivated pseudovirus particles. The irreversibility effect was revealed by the observation that pseudoviruses first treated with CV-N and then washed to remove all soluble lectin did not recover infectivity.

Screen for New Antimicrobial Natural Products from the NCI Program for Natural Product Discovery Prefractionated Extract Library.

The continuing emergence of antibiotic-resistant microbes highlights the need for the identification of new chemotypes with antimicrobial activity. One of the most prolific sources of antimicrobial molecules has been the systematic screening of natural product samples. The National Institute of Allergy and Infectious Diseases and the National Cancer Institute here report a large screen of 326,656 partially purified natural product fractions against a panel of four microbial pathogens, resulting in the identification of >3000 fractions with antifungal and/or antibacterial activity.

Biochemical Discovery, Intracellular Evaluation, and Crystallographic Characterization of Synthetic and Natural Product Adenosine 3',5'-Cyclic Monophosphate-Dependent Protein Kinase A (PKA) Inhibitors.

The recent demonstration that adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase A (PKA) plays an oncogenic role in a number of important cancers has led to a renaissance in drug development interest targeting this kinase. We therefore have established a suite of biochemical, cell-based, and structural biology assays for identifying and evaluating new pharmacophores for PKA inhibition. This discovery process started with a 384-well high-throughput screen of more than 200,000 substances, including fractionated natural product extracts.

An approach to rapid distributed manufacturing of broad spectrum anti-viral griffithsin using cell-free systems to mitigate pandemics.

This study describes the cell-free biomanufacturing of a broad-spectrum antiviral protein, griffithsin (GRFT) such that it can be produced in microgram quantities with consistent purity and potency in less than 24 h. We demonstrate GRFT production using two independent cell-free systems, one plant and one microbial. Griffithsin purity and quality were verified using standard regulatory metrics.

National Cancer Institute (NCI) Program for Natural Product Discovery: Exploring NCI-60 Screening Data of Natural Product Samples with Artificial Neural Networks.

National Cancer Institute (NCI) Program for Natural Product Discovery is a new initiative aimed at creating new technologies for natural product-based drug discovery. Here, we present the development of a neural network-based bioinformatics platform for visualization and analysis of natural product high-throughput screening data using the NCI's 60 human tumor cell anticancer drug screen. We demonstrate how the tool enables visualization of similar patterns of response that can be parsed both chemically and taxonomically, grouping NCI-60 biological profiles in one easy-to-use bioinformatics interface.

Cyanovirin-N binds to select SARS-CoV-2 spike oligosaccharides outside of the receptor binding domain and blocks infection by SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped positive stranded RNA virus which has caused the recent deadly pandemic called COVID-19. The SARS-CoV-2 virion is coated with a heavily glycosylated Spike glycoprotein which is responsible for attachment and entry into target cells. One, as yet unexploited strategy for preventing SARS-CoV-2 infections, is the targeting of the glycans on Spike.

Photochemical Dimerization of Plakinidine B Leads to Potent Inhibition of the E3 Ubiquitin-Protein Ligase CBL-B.

A new dimeric alkaloid plakoramine A [(±)-] was identified from a marine sponge sp. Chiral-phase HPLC separation of (±)- led to the purified enantiomers (+)- and (-)- which both potently inhibited CBL-B E3 ubiquitin ligase activities. The absolute configurations of the enantiomers were determined by quantum chemical calculations.

Dentithecamides A-H, Diacylated Zoanthoxanthin Derivatives with PAX3-FOXO1 Inhibitory Activity from the Hydroid .

Chemical investigation of the marine hydroid led to the identification of eight new diacylated zoanthoxanthin alkaloids, named dentithecamides A-H (-), along with three previously reported analogues, zoamides B-D (-). The structures of compounds - were elucidated by spectroscopic and spectrometric analyses, including IR, HRESIMS, and NMR experiments, and by comparison with literature data. Compounds - are the first zoanthoxanthin alkaloids to be reported from a hydroid.

Physicochemical characterization of the recombinant lectin scytovirin and microbicidal activity of the SD1 domain produced in rice against HIV-1.

Rice-produced SD1 retains its physicochemical properties and provides efficient pre-exposure HIV-1 prophylaxis against infection in vitro. Scytovirin (SVN) is an HIV-neutralizing lectin that features two structural domains (SD1 and SD2) that bind to HIV-1 envelope glycoproteins. We expressed SD1 in rice seeds as a potential large-scale production platform and confirmed that rice-derived SD1 binds the HIV-1 envelope glycoprotein gp120 in vitro.