DrTx(1-42), a C-terminally truncated analogue of drosotoxin, is a candidate of analgesic drugs.
Drosotoxin is an engineered tetrodotoxin-resistant (TTX-R) sodium channel-specific blocker with a non-toxic structural core (Zhu et al. Biochem Pharmacol 2010; 80:1296-302). Here, we report the discovery and functional characterization of a carboxyl-terminally truncated analogue of drosotoxin (named DrTx(1-42)) which selectively inhibited dorsal root ganglion (DRG) neuron TTX-R sodium current (I(Na)) with an IC(50) value of 1.74±0.07μM. Consistent with this effect, DrTx(1-42) significantly attenuates inflammatory hyperalgesia of mice in a formalin-induced pain model with stronger potency than indomethacin, a nonsteroidal anti-inflammatory and analgesic drug. Our mutational experiments indicate that the N-turn insertion is an essential functional determinant for the emergence of neurotoxicity from a non-toxic antifungal scaffold.
Group of Animal Innate Immunity, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Chaoyang District, Beijing, China. Zhusy@ioz.ac.cn
Shunyi
S
Zhu
Lan
L
Luo
Ping
P
Li
Bin
B
Gao
Limei
L
Zhu
Yuzhe
Y
Yuan
D000700:Analgesics / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D026941:Sodium Channel Blockers / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D013779:Tetrodotoxin / Q000494:pharmacology
D000700:Analgesics; C555147:DrTx(1-42); D011993:Recombinant Fusion Proteins; D026941:Sodium Channel Blockers; C552535:drosotoxin; D013779:Tetrodotoxin