Lab-made nerve-signal fragment (DSFVGL)

What this is

DSFVGL is a synthetic six-amino-acid peptide derived from the central region of neurokinin A (NKA), a naturally occurring neuropeptide in the tachykinin family. Neurokinin A is a ten-residue peptide (HKTDSFVGLM) released in the nervous system and peripheral tissues; DSFVGL corresponds to positions 4–9 of that sequence, retaining the core recognition motif while dropping the N-terminal HKT triplet and the C-terminal methionine. It was catalogued in the ChEMBL bioactivity database (CHEMBL2390989) as a ligand for the tachykinin receptor 2 (TACR2, also called NK2R), with an IC50 of 3.5 nM in a TACR2 binding assay.

What it does

TACR2 is a G protein-coupled receptor (GPCR) that is the principal receptor for neurokinin A in the body. It is expressed prominently in airway and intestinal smooth muscle and in several brain regions including the hippocampus and substantia nigra. Activation of TACR2 triggers downstream signalling through Gq/G11 (raising intracellular calcium via IP3) and, in some cell types, through Gs (raising cAMP). Physiologically, NK2R activation causes bronchoconstriction, promotes intestinal motility, and modulates nociceptive and mood-related circuits. DSFVGL, by engaging the same receptor binding site, can activate these same pathways in experimental settings.

Evidence

• Human: No published human clinical trials specifically for DSFVGL. NK2R agonists and antagonists as a class have been evaluated clinically in asthma and mood disorders (e.g., the NK2R antagonist saredutant in depression trials), but DSFVGL itself has not been advanced to human studies.
• Animal: No published animal studies identified specifically for DSFVGL.
• In vitro: IC50 = 3.5 nM at human TACR2 (ChEMBL CHEMBL2390989 bioassay entry). Structure-activity studies on the parent NKA(4-10) heptapeptide (DSFVGLM) show that this core segment retains potency comparable to full-length NKA at NK2R, with the N-terminal HKT triplet being dispensable for receptor activation (Madsen and colleagues 2023; Petersen and colleagues 2025).

Mechanism

TACR2 is a class A GPCR. Neurokinin A and its fragments engage the orthosteric binding pocket via a dual-site mechanism: the C-terminal region inserts into the transmembrane domain (TMD) cavity, while N-terminal residues interact with extracellular loop 2 (ECL2). Cryo-EM structural analysis of the NKA–NK2R–Gq complex at 2.7 Å resolution (Sun and colleagues, Cell Discovery 2022) showed that the conserved C-terminal residues of NKA form a polar interaction network with TM2, TM3, and TM7 residues of NK2R, and that Y266 in TM7 makes a hydrogen bond with the amide of the C-terminal methionine of NKA. DSFVGL lacks this terminal methionine; its 3.5 nM IC50 at TACR2 suggests the six-residue core retains substantial binding energy, likely through contacts with the aromatic F (Phe6) and the conserved Gly-Leu motif that position the peptide within the TMD cavity. The Gαq coupling activates phospholipase C, generating IP3 and diacylglycerol, leading to calcium mobilisation and protein kinase C activation.

Related peptides

• Neurokinin A — the ten-residue parent peptide (HKTDSFVGLM) from which DSFVGL is derived; primary endogenous agonist at NK2R with pKi ~8–9 at human TACR2.
• NKA(4-10) / DSFVGLM — the seven-residue minimal active fragment of NKA that retains potency comparable to full-length NKA at NK2R in functional assays; DSFVGL is a further C-terminal truncation of this fragment.
• GR64349 — a synthetic NK2R-selective agonist based on a modified NKA(3-10) scaffold ([Lys3,Gly8,R-γ-lactam-Leu9]-NKA(3-10)); reported as one of the most selective NK2R agonists characterized to date (Perdona and colleagues 2019).