Inhibitor Peptides

Inhibitor Peptides — Frequently Asked Questions

When the target interface is large, flat, or lacks a deep pocket — typical of protein–protein interactions, transcription-factor coactivator binding, or viral-entry surfaces. Peptides also win for substrate-competitive inhibition of proteases / kinases where the natural recognition motif must be preserved, and for probing PPIs during early target validation.

Start from the binding interface: extract the 4–7 hotspot residues from the partner protein, graft them into a stable scaffold, then constrain the α-helix (stapling, lactam bridge, hydrocarbon crosslink) or β-turn (cyclization, D-Pro / D-Pro) to recover binding entropy. Validated wins include p53–MDM2 (PMI / ATSP-7041), Bcl-2 (BH3 mimetics), and PD-1/PD-L1.

A peptide that mimics the high-energy tetrahedral intermediate of an enzyme reaction. Replacing the scissile amide bond with a non-cleavable isostere (hydroxyethylene, statine, norstatine, α-ketoamide, phosphinate) gives tight-binding inhibitors used in HIV protease, HCV NS3/4A, renin, MMP, and SARS-CoV-2 Mpro drug design.

Phosphoserine / phosphothreonine / phosphotyrosine (pSer / pThr / pTyr) are coupled directly during SPPS using protected phospho-amino-acid building blocks (e.g. Fmoc-Ser(PO(OBn)OH)-OH). Non-hydrolyzable analogues (phosphonomethyl, phosphonophenyl, F2Pmp) replace P-O to give phosphatase-resistant substrate-competitive inhibitors.

Ki is the cleanest biophysical constant (substrate-independent binding affinity). IC50 depends on assay substrate concentration and is useful for ranking but rarely comparable across labs. Cellular IC50 (target engagement + functional readout) is the most predictive for lead prioritization, but cell-penetration and stability must be considered before interpreting it.

Yes. We install α-methyl, α-aminoisobutyric acid (Aib), pentenyl-glycine / S5-olefin pairs, and lactam bridges at i, i+4 or i, i+7 spacing to stabilize α-helices. Validated scaffolds include PMI / ATSP-7041 (MDM2), BID-BH3, and stapled ApoA-I mimetics — delivered with HPLC + MS + CD helical-content QC.