Su Shiwei, Chen Liqing, Yang Menglan, Liang Dan, Ke Bixia, Liu Zhongqiu, Ke Changwen, Liao Guochao, Liu Liang, Luo Xiang
Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine Guangzhou China
State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine Guangzhou China
RSC Med Chem. 2022 Oct 14;14(1):47-55. doi: 10.1039/d2md00298a. eCollection 2023 Jan 25.
Toll-like receptor 4 (TLR4) is a reliable target for the development of vaccine adjuvants. To identify novel TLR4 ligands with improved immunological properties for use as adjuvants for a RBD-hFc based SARS-CoV-2 vaccine, herein, natural monophosphoryl lipid A (MPLA) and nine of its derivatives were designed and synthesized. Immunological evaluation showed that compounds 1, 3, 5 and 7 exhibited comparative or better adjuvant activity than clinically used Al adjuvants, and are expected to be a promising platform for the development of new adjuvants used for a RBD-hFc based SARS-CoV-2 vaccine. Preliminary structure-activity relationship analysis of the MPLA derivatives showed that the replacement of the functional groups at the C-1, C-4' or C-6' position of MPLA has an effect on its biological activity. In addition, we found that the combination of MPLA and Al was feasible for immunotherapy and could further enhance immune responses, providing a new direction toward the immunological enhancement of RBD-hFc based SARS-CoV-2 vaccines.
Toll样受体4（TLR4）是疫苗佐剂开发的可靠靶点。为了鉴定具有改善免疫特性的新型TLR4配体，用作基于RBD-hFc的SARS-CoV-2疫苗的佐剂，在此设计并合成了天然单磷酰脂质A（MPLA）及其九种衍生物。免疫学评估表明，化合物1、3、5和7表现出与临床使用的铝佐剂相当或更好的佐剂活性，有望成为开发用于基于RBD-hFc的SARS-CoV-2疫苗的新型佐剂的有前景平台。对MPLA衍生物的初步构效关系分析表明，MPLA的C-1、C-4'或C-6'位官能团的取代对其生物活性有影响。此外，我们发现MPLA与铝联合用于免疫治疗是可行的，并且可以进一步增强免疫反应，为基于RBD-hFc的SARS-CoV-2疫苗的免疫增强提供了新方向。
