Natural products
11 articles
Cell-penetrating peptide conjugation broadens and strengthens lasso peptide antibiotics
- Lasso peptide antibiotics such as citrocin and microcin J25 inhibit bacterial RNA polymerase but rely on membrane transporters to get in, narrowing their spectrum and inviting resistance.
- Attaching a cell-penetrating peptide to the loop gave conjugates active against all four Gram-negative ESKAPE pathogens tested and more potent than the unmodified parents.
- E. coli uptake studies suggest entry by both transporter-dependent and transporter-independent routes.
Four-for-four Gram-negative ESKAPE coverage suggests transporter-dependent uptake, not the RNAP pharmacophore, was the limiting factor. A cationic CPP is a blunt fix, though: expect serum binding, protease exposure and mammalian membrane liability, so selectivity indices and stability data will decide whether it beats engineering the loop for better transporter recognition. Grafting onto the threaded scaffold looks tractable.
Milk thistle supplement raises resmetirom exposure in a rat MASH model
- Milk thistle (silybin) given with the liver-directed THR-β agonist resmetirom to MCD-diet MASH rats increased resmetirom plasma exposure and lowered its apparent oral clearance.
- In rat liver microsomes, the extract markedly slowed resmetirom depletion, pointing to inhibited hepatic metabolism.
- The combination also improved liver enzymes, lipids and histology more than either agent alone, though the exposure increase flags a possible interaction.
A rat MCD-diet model is a rough proxy for human MASH, and a rat microsomal slowdown says little about the CYP and transporter picture in people. Still, higher exposure in a liver-directed drug is exactly what I'd chase: is the extra efficacy just more drug on board, and does the safety margin shrink with it? Needs human PK before anyone reads it as benefit.
Engineered polyene M16 distinguishes ergosterol from cholesterol, keeping antifungal activity while sparing host cells and kidneys in mice
- Mandimycin M16, built on a 5 + 1 polyene scaffold, was designed to overcome amphotericin B's poor discrimination between fungal and mammalian sterols.
- It recognizes the conjugated diene unique to ergosterol, shows no measurable cholesterol binding, and kills fungi rapidly across a panel of WHO priority pathogens.
- In vitro and in mice, hemolysis, cytotoxicity and kidney toxicity were undetectable at the doses tested.
- In disseminated infection models, it beat liposomal amphotericin B at matched doses, with large fungal burden reductions and full survival.
Undetectable nephrotoxicity sounds too clean for a polyene, and I'd want to know how long they dosed. Short mouse regimens rarely reproduce the cumulative tubular damage that limits amphotericin B over weeks in patients. Before taking M16 forward, I'd want repeat-dose tox with exposure data and a workable formulation; the cholesterol-sparing mechanism is convincing, but the safety margin is unproven.
Cinchona-derived ammonium salts give long-lasting, sensory-selective nerve block
- Ammonium salts built on natural cinchona alkaloids were explored as local anesthetics; the bicyclic quincoridine skeleton beat acyclic and monocyclic analogues.
- Lead CLA-1-3 blocked the rat sciatic nerve for more than 50 hours and potently inhibited voltage-gated sodium channels.
- A second compound, CLA-3-5, gave a sensory-selective block lasting up to about 3 hours at 0.30–0.60% concentration.
Duration is the headline, but the permanently charged ammonium is the more interesting design choice: it should slow washout from the injection site, which probably explains the long action. For anything that lasts over 50 hours, though, I'd look at local neurotoxicity and myotoxicity data before the efficacy curves.
Cinchona Alkaloids-Derived Ammonium Salts for Long-Acting and Sensory-Selective Nerve Blockades ↗
Millepachine hybrid hits tubulin and HDAC8 together in ovarian cancer models
- The natural product millepachine was fused with a key HDAC-inhibitor pharmacophore to build dual tubulin/HDAC inhibitors.
- Lead compound 6 was broadly antiproliferative across 12 cancer lines, inhibited tubulin polymerisation and HDAC8, and was selective for HDAC8 over HDAC1, 4 and 6.
- It suppressed tumour growth in an ovarian cancer xenograft with a favourable safety profile.
HDAC8 is a less crowded choice than the usual HDAC6/class I pairing, and pairing it with a tubulin binder is mechanistically coherent. My worry is the classic one for dual hybrids: the two activities rarely scale together, so I'd want evidence that HDAC8 inhibition, not just the tubulin arm, contributes to the in vivo effect.
Ferulic acid-based PROTAC degrades TLR4 to protect endothelial cells
- Six PROTACs built on ferulic acid, a weakly active natural product, were tested for TLR4 degradation and migration in HUVECs.
- The lead, FP-4, degraded TLR4 and dampened TLR4/MyD88–NF-κB signaling plus TNF-α, ICAM-1 and VCAM-1 expression.
- Protection was also seen in zebrafish, extending PROTAC use beyond oncology.
Using a PROTAC to rescue a weak natural-product binder is clever, but TLR4 is a membrane receptor and the evidence here is thin on which E3 ligase is engaged and on ternary-complex dependence. I'd ask for rescue experiments with ligase and proteasome inhibitors before believing the mechanism.
Sulfonium-modified pneumocandins overcome Cryptococcus' intrinsic echinocandin resistance
- Covalent sulfonium modification of the natural pneumocandin B0 scaffold gave derivatives active against Candida and able to reverse innate Cryptococcus neoformans resistance (MIC as low as 2 μg/mL).
- The modification raised fungal membrane permeability and caused depolarization while strengthening glucan synthase inhibition.
- Leads 3h and 5h showed low resistance potential, good safety and PK, and in vivo antifungal efficacy.
Echinocandins have never covered Cryptococcus, so adding a membrane-active cationic handle to restore activity is a smart reuse of a validated scaffold. The risk is that membrane disruption narrows the selectivity window, so host-cell toxicity data and the mechanism split deserve a close read.
Tuned lanosterol derivative crosses the BBB and curbs Aβ burden in AD mice
- Lanosterol inhibits protein aggregation but has poor physicochemical and PK properties, so the authors tuned the hydrophilic–lipophilic balance around the 3-hydroxyl and the aliphatic side chain.
- Systematic screening gave compound 10, with markedly better metabolic stability and drug-like properties.
- Oral dosing of 10 rescued memory deficits and reduced Aβ burden in an Alzheimer's mouse model.
Natural-product sterols rarely survive their first PK table, so getting oral CNS exposure by tuning polarity around the 3-OH and side chain is the part I'd borrow. The open question is mechanism: efficacy in one mouse model is easy to over-read, and I'd want target engagement and sterol-pathway off-target data before getting excited.
Azaphilone Probe Maps Reactive Lysines Across Live Bacterial Proteomes
- SCL-alkyne, a simplified azaphilone derived from the natural product sclerotiorin, was designed to profile lysine reactivity proteome-wide in bacteria.
- It was highly lysine-selective in vitro and in live E. coli; most engaged sites were lysines or protein N-termini, and only a small subset of reactive lysines sat in functional regions.
- Enrichment analysis pointed to bacterial chemotaxis as a major target pathway, which was then confirmed.
Covalent ligand discovery has been cysteine-centric, and lysine-directed scaffolds beyond sulfonyl fluorides and activated esters are scarce, so a natural-product-derived option is appealing. The observation that few reactive lysines are functional is a sober reminder that reactivity is cheap and function is not. As an E. coli preprint it is a starting point for covalent fragments, not a lead.
Fragment Growing Explored to Improve a Natural Cysteine-Sulfoxide BACE-1 Inhibitor
- Alliin, a natural cysteine-sulfoxide that chelates BACE-1's catalytic dyad, has poor pharmacokinetics, limiting its use as a drug lead.
- Researchers used a fragment-growing strategy guided by molecular dynamics simulations to build out from this core, aiming to improve affinity and drug-like properties.
- The campaign remains an early-stage computational effort, not a validated clinical candidate.
Starting from a food-derived fragment like alliin is seductive — built-in tox clearance, cheap chirality — but BACE-1 is where good binders go to die clinically (verubecestat, lanabecestat, atabecestat all crashed on safety/efficacy despite clean biochemistry). Growing a fragment computationally is the easy 80%; without disclosed SPR/ITC or crystallography backing the MD poses, I'd treat the affinity gains as hypotheses, not results.
Novel Plant Metabolites Show Isoform-Selective Inhibition of Cav3.1 Calcium Channels
- Five new natural products, hyreptaones A-E (1-5), were isolated from the plant Hypericum reptans, defining a novel class of 1,2-seco-bicyclic polyprenylated acylphloroglucinols (BPAPs).
- Compounds 1-3 are the first 1,2-seco-BPAPs shown to derive from rare 3,3-diisoprenylated BPAP precursors, while 4 and 5 feature an unusual spirocyclic 6/5/5 ring system formed by further cyclization of the 1,2-seco-BPAP core.
- Structures were established using spectroscopic analysis together with X-ray crystallography.
- All five compounds preferentially inhibited the Cav3.1 T-type calcium channel over other T-type channel subtypes, indicating isoform selectivity.
- Compounds 4 and 5 additionally showed state-dependent modulation of Cav3.1 gating, marking them as a new class of Cav3.1 allosteric modulators.
Isoform selectivity within the T-type family (Cav3.1 vs 3.2/3.3) is exactly what's been missing from this space — most T-type blockers I've seen are promiscuous pore-blockers with narrow therapeutic windows, so five compounds hitting Cav3.1 preferentially is worth a second look. The state-dependent gating modulation in 4/5 is the more interesting story mechanistically: allosteric, conformation-selective action tends to buy better selectivity and fewer off-target liabilities than brute-force channel block. That said, I'm skeptical this scaffold is a med-chem starting point rather than a probe — a spirocyclic 6/5/5 BPAP that needed X-ray to nail down stereochemistry screams synthetic bottleneck, and five compounds isolated from one plant is not a supply chain, it's a bottleneck waiting to happen. I'd want SAR against simplified, truncated analogs before believing this is optimizable rather than just interesting.