De novo discovery delivers first-in-class ligands for three hard targets
In preprints: RaPID-derived macrocyclic peptides antagonize CXCR4 with nanomolar affinity; CYP8B1 inhibitors offer a first-in-class MASLD strategy; brain-penetrant DELC2 modulates neuroinflammation in Alzheimer's models.
- In a preprint, RaPID-based de novo macrocyclic peptide discovery generated CXCR4-selective antagonists with nanomolar affinity that bind the orthosteric pocket and block CXCR4-driven HIV entry and chemokine-driven migration. Self-reported m:…5428
- In a preprint, researchers developed small-molecule inhibitors of the liver-exclusive enzyme CYP8B1 as a first-in-class strategy for MASLD, with lead compounds remodeling gut microbiota and bile acid profiles in vivo. Self-reported m:…5050
- In a preprint, the novel inhibitor DELC2 binds the CHI3L1 glycan-recognition groove, blocks CHI3L1-RAGE signaling, and - with oral dosing in 5xFAD mice - achieved sustained unbound brain exposure, improved cognition, and reduced amyloid-beta pathology. Self-reported m:…7493
Peptides for the hard-to-drug GPCRs
Class A GPCRs have been considered challenging targets for peptide drugs because they offer limited solvent-exposed surface area. In a preprint, researchers validate RaPID-based de novo macrocyclic peptide discovery against this family, identifying CXCR4-selective antagonists with nanomolar affinity that bind within the orthosteric pocket. m:…5428
The functional readouts go beyond binding: the peptides effectively inhibited orthosteric signaling, chemokine-driven cell migration, and CXCR4-driven HIV entry. The authors' broader claim is platform-level - a scalable route to novel ligands for other GPCR superfamily members - and it rests on this first demonstration holding up under replication. Notably, the peptides blocked three distinct CXCR4 functions - signaling, migration, and viral entry - rather than just occupying the receptor. m:…5428
A first-in-class lever for fatty liver disease
A second preprint introduces what the authors describe as a first-in-class therapeutic strategy for metabolic dysfunction-associated steatotic liver disease (MASLD): targeting CYP8B1, a liver-exclusive enzyme. The team developed an enzyme-coupled fluorescence assay enabling high-throughput screening for CYP8B1-specific inhibitors, then applied structure-based drug design to identify small molecules. m:…5050
In vivo, the lead CYP8B1 inhibitors remodeled gut microbiota and bile acid profiles to correct metabolic disease in the authors' models. The specificity angle is the point: a liver-exclusive enzyme offers a narrow target with, in principle, fewer off-tissue effects - though that principle remains to be tested beyond these preclinical models. Nothing here is a treatment claim. m:…5050
An oral, brain-penetrant modulator for Alzheimer's neuroinflammation
The third preprint identifies DELC2, a novel brain-penetrant inhibitor of CHI3L1 - a protein elevated in Alzheimer's disease - designed against the glycan-recognition groove, in an aromatic-hydrophobic pocket centered on Trp99 and Trp352. DELC2 blocks the CHI3L1-RAGE interaction and suppresses CHI3L1-induced inflammatory signaling, restoring glial function in the authors' assays. m:…7493
The preclinical package: oral DELC2 achieved sustained unbound brain exposure in 5xFAD mice, improved cognitive performance, and reduced amyloid-beta pathology. Brain penetration plus oral dosing is the combination that makes this notable as a drug-discovery matter - most CNS candidates fail on one of the two. Again, preclinical only. m:…7493
Undruggable is a statement about tools
Three targets, three discovery routes: de novo peptide libraries, structure-based small molecules, groove-targeted design. The common thread is that undruggable keeps being a statement about the tools available, not the targets themselves. All three are preprints reporting preclinical results; the distance from here to a medicine is measured in years and failed trials, and none of these papers claims otherwise. What they do claim - and document - is that the first step, a potent and selective ligand, is now reachable for targets the field had written off. m:…5428 m:…5050 m:…7493
Platforms versus molecules
Each paper sells two things: a molecule and a platform. The RaPID paper's CXCR4 antagonists are the proof; the platform claim - a scalable route to ligands for other class A GPCR members - is what a discovery team would actually adopt. The CYP8B1 paper similarly pairs lead inhibitors with a reusable high-throughput fluorescence screening assay. The CHI3L1 paper is molecule-first, with groove-targeted design against the glycan-recognition groove as the transferable idea. m:…5428 m:…5050 m:…7493
The failure mode to watch, and this is analysis: platform claims routinely outrun their first demonstration. Nanomolar affinity, remodeled bile-acid profiles, and improved mouse cognition are real reported results - but GPCR peptide delivery, liver-enzyme selectivity in humans, and CNS translation have each ended promising programs before. These papers earn attention; they do not earn de-risking. m:…5428 m:…5050 m:…7493
What is still unresolved
- Whether the RaPID platform generalizes to other class A GPCR targets.
- Safety and selectivity profile of CYP8B1 inhibition beyond the reported models.
- Whether DELC2's effects replicate in additional Alzheimer's models and progress toward clinical testing.
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