Stapling Cysteine[2,4] Disulfide Bond of α-Conotoxin LsIA and Its Potential in Target Delivery

Author:

Sun Xin1,Hu Jiangnan1,Ren Maomao1,Chang Hong2,Zhangsun Dongting1,Zhang Baojian1ORCID,Dong Shuai1ORCID

Affiliation:

1. Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China

2. Hainan Academy of Inspection and Testing, Haikou 570228, China

Abstract

α-Conotoxins, as selective nAChR antagonists, can be valuable tools for targeted drug delivery and fluorescent labeling, while conotoxin-drug or conotoxin-fluorescent conjugates through the disulfide bond are rarely reported. Herein, we demonstrate the [2,4] disulfide bond of α-conotoxin as a feasible new chemical modification site. In this study, analogs of the α-conotoxin LsIA cysteine[2,4] were synthesized by stapling with five linkers, and their inhibitory activities against human α7 and rat α3β2 nAChRs were maintained. To further apply this method in targeted delivery, the alkynylbenzyl bromide linker was synthesized and conjugated with Coumarin 120 (AMC) and Camptothecin (CPT) by copper-catalyzed click chemistry, and then stapled between cysteine[2,4] of the LsIA to construct a fluorescent probe and two peptide-drug conjugates. The maximum emission wavelength of the LsIA fluorescent probe was 402.2 nm, which was essentially unchanged compared with AMC. The cytotoxic activity of the LsIA peptide-drug conjugates on human A549 was maintained in vitro. The results demonstrate that the stapling of cysteine[2,4] with alkynylbenzyl bromide is a simple and feasible strategy for the exploitation and utilization of the α-conotoxin LsIA.

Funder

National Natural Science Foundation of China

Hainan Provincial Natural Science Foundation of China

Scientific Research Foundation of Hainan University

Publisher

MDPI AG

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