The Marine Cyanobacterial Metabolite Gallinamide A Is a Potent and Selective Inhibitor of Human Cathepsin L

A number of marine natural products are potent inhibitors of proteases, an important drug target class in human diseases. Hence, marine cyanobacterial extracts were assessed for inhibitory activity to human cathepsin L. Herein, we have shown that gallinamide A potently and selectively inhibits the human cysteine protease cathepsin L. With 30 min of preincubation, gallinamide A displayed an IC₅₀ of 5.0 nM, and kinetic analysis demonstrated an inhibition constant of <i>k</i>_i = 9000 ± 260 M^–1 s^–1. Preincubation–dilution and activity-probe experiments revealed an irreversible mode of inhibition, and comparative IC₅₀ values display a 28- to 320-fold greater selectivity toward cathepsin L than closely related human cysteine cathepsin V or B. Molecular docking and molecular dynamics simulations were used to determine the pose of gallinamide in the active site of cathepsin L. These data resulted in the identification of a pose characterized by high stability, a consistent hydrogen bond network, and the reactive Michael acceptor enamide of gallinamide A positioned near the active site cysteine of the protease, leading to a proposed mechanism of covalent inhibition. These data reveal and characterize the novel activity of gallinamide A as a potent inhibitor of human cathepsin L

Presentation_1_4-(Hydroxymethyl)catechol Extracted From Fungi in Marine Sponges Attenuates Rheumatoid Arthritis by Inhibiting PI3K/Akt/NF-κB Signaling.pdf

<p>Rheumatoid arthritis (RA) is a progressive autoimmune disease specific to synovial joints; it causes joint damage and other systemic abnormalities, thereby leading to physical disability and early mortality. Marine sponge-derived fungi, Pestalotiopsis sp., secrete immunosuppressive compounds in the culture broth. In the present study, we isolated 4-(hydroxymethyl)catechol (4-HMC) from these fungal species, and evaluated its anti-RA effects using a murine collagen-induced arthritis model and tumor necrosis factor-α-stimulated human RA synovial fibroblasts. Oral 4-HMC administration decreased the clinical arthritis score, paw thickness, histologic and radiologic changes, and serum IgG1 and IgG2a levels. It prevented the proliferation of helper T (Th) 1/Th17 CD4⁺ lymphocytes isolated from inguinal lymph nodes, thereby reducing inflammatory cytokine production in CIA mice. It decreased the expression of inflammatory mediators, including cytokines and matrix metalloproteinases (MMPs), both in vitro and in vivo. We observed that 4-HMC suppresses Th immune responses and MMP expression to inhibit inflammatory cytokine production in human RA synovial fibroblasts by modulating the PI3K/Akt/NF-κB pathway. These results verify the anti-RA potential of 4-HMC.</p

Anithiactins A–C, Modified 2‑Phenylthiazoles from a Mudflat-Derived <i>Streptomyces</i> sp.

Intensive investigation of the chemical components of a <i>Streptomyces</i> sp. isolated from mudflat sediments collected on the southern coast of the Korean peninsula led to the isolation of three new compounds, anithiactins A–C (<b>1</b>–<b>3</b>). The chemical structures of anithiactins A and C were determined by interpretation of NMR data analyses, while the chemical structure of anithiactin B was established from a combination of NMR spectroscopic and crystallographic data analyses. The structure of anithiactin A was also confirmed by total synthesis. These three anithiactins displayed moderate acetylcholinesterase inhibitory activity with no significant cytotoxicity

Identification of Antiangiogenic Potential and Cellular Mechanisms of Napyradiomycin A1 Isolated from the Marine-Derived <i>Streptomyces</i> sp. YP127

Angiogenesis is the process of new blood vessel formation. Excessive angiogenesis is a critical factor in the progression of cancer, macular degeneration, and other chronic inflammatory diseases. When investigating the effects of crude extracts of cultured marine microorganisms, an extract of the cultured <i>Streptomyces</i> sp. YP127 strain was found to inhibit human umbilical vein endothelial cell (HUVEC) tube formation. Bioassay-guided fractionation and spectroscopic data analyses led to the identification of napyradiomycin A1 (<b>1</b>) as an antiangiogenic component of the extract. Compound <b>1</b> inhibited HUVEC tube formation in a concentration-dependent manner. It inhibited endothelial cell proliferation but did not affect human dermal fibroblast proliferation. Compound <b>1</b> also suppressed migration and invasion of vascular endothelial cells. In addition, compound <b>1</b> suppressed vascular endothelial cadherin expression and increased the permeability of the endothelial cell membrane. These results suggested that compound <b>1</b> modulates cell permeability and inhibits the angiogenesis of endothelial cells

Marine Natural Product Honaucin A Attenuates Inflammation by Activating the Nrf2-ARE Pathway

The cyanobacterial marine natural product honaucin A inhibits mammalian innate inflammation in vitro and in vivo. To decipher its mechanism of action, RNA sequencing was used to evaluate differences in gene expression of cultured macrophages following honaucin A treatment. This analysis led to the hypothesis that honaucin A exerts its anti-inflammatory activity through activation of the cytoprotective nuclear erythroid 2-related factor 2 (Nrf2)-antioxidant response element/electrophile response element (ARE/EpRE) signaling pathway. Activation of this pathway by honaucin A in cultured human MCF7 cells was confirmed using an Nrf2 luciferase reporter assay. In vitro alkylation experiments with the natural product and <i>N</i>-acetyl-l-cysteine suggest that honaucin A activates this pathway through covalent interaction with the sulfhydryl residues of the cytosolic repressor protein Keap1. Honaucin A presents a potential therapeutic lead for diseases with an inflammatory component modulated by Nrf2-ARE

Monanchosterols A and B, Bioactive Bicyclo[4.3.1]steroids from a Korean Sponge <i>Monanchora</i> sp.

Chemical investigation of a Korean marine sponge, <i>Monanchora</i> sp., led to the isolation of three new steroids (<b>1</b>–<b>3</b>). Compounds <b>1</b> and <b>2</b>, designated as monanchosterols A and B, respectively, represent the first examples of steroids possessing the bicyclo[4.3.1] A/B ring system from a natural source. Compounds <b>1</b>–<b>3</b> were investigated for their anti-inflammatory activity by evaluating their inhibitory effects on the mRNA expression of IL-6, TNF-α, and COX-2 in the LPS-stimulated murine RAW264.7 macrophage cells. Compounds <b>2</b> and <b>3</b> exhibited significant inhibitory effects on the mRNA expression of IL-6 without notable cytotoxicity to the cells in a dose-dependent manner

Heterologous Production of 4‑<i>O</i>‑Demethylbarbamide, a Marine Cyanobacterial Natural Product

Heterologous expression of the barbamide biosynthetic gene cluster, obtained from the marine cyanobacterium <i>Moorea producens</i>, in the terrestrial actinobacterium <i>Streptomyces venezuelae</i>, resulted in the production of a new barbamide congener 4-<i>O</i>-demethylbarbamide, demonstrating the potential of this approach for investigating the assembly and tailoring of complex marine natural products

Phosphoiodyns A and B, Unique Phosphorus-Containing Iodinated Polyacetylenes from a Korean Sponge <i>Placospongia</i> sp.

Two unprecedented phosphorus-containing iodinated polyacetylenes, phosphoiodyns A and B (<b>1</b>–<b>2</b>), were isolated from a Korean marine sponge <i>Placospongia</i> sp. Their structures were elucidated by spectroscopic data analysis. Phosphoiodyn A exhibited potent agonistic activity on human peroxisome proliferator-activated receptor delta (hPPARδ) with an EC₅₀ of 23.7 nM

Acredinones A and B, Voltage-Dependent Potassium Channel Inhibitors from the Sponge-Derived Fungus <i>Acremonium</i> sp. F9A015

Two new benzophenones, acredinones A (<b>1</b>) and B (<b>2</b>), were isolated from a marine-sponge-associated <i>Acremonium</i> sp. fungus. Their chemical structures were elucidated on the interpretation of spectroscopic data. The structure of <b>1</b> was confirmed by palladium-catalyzed hydrogenation, followed by spectroscopic data analysis. Acredinones A (<b>1</b>) and B (<b>2</b>) inhibited the outward K⁺ currents of the insulin secreting cell line INS-1 with IC₅₀ values of 0.59 and 1.0 μM, respectively

Acredinones A and B, Voltage-Dependent Potassium Channel Inhibitors from the Sponge-Derived Fungus <i>Acremonium</i> sp. F9A015

Two new benzophenones, acredinones A (<b>1</b>) and B (<b>2</b>), were isolated from a marine-sponge-associated <i>Acremonium</i> sp. fungus. Their chemical structures were elucidated on the interpretation of spectroscopic data. The structure of <b>1</b> was confirmed by palladium-catalyzed hydrogenation, followed by spectroscopic data analysis. Acredinones A (<b>1</b>) and B (<b>2</b>) inhibited the outward K⁺ currents of the insulin secreting cell line INS-1 with IC₅₀ values of 0.59 and 1.0 μM, respectively