BIOORGANIC & MEDICINAL CHEMISTRY
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2021
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IF 3.641
Yaping Cheng,Jingyuan Wu,Ying Han,Jingyao Xu,Yifan Da,Qian Zhao,Guoying Guo,Yani Zhou,Yimin Chen,Jinghong Liu,Huayao Chen,Xianxing Jiang,Xiaoqing Cai
Covalent target modulation with small molecules has been emerging as a promising strategy for drug discovery. However, covalent inhibitory antibody remains unexplored due to the lack of efficient strategies to engineer antibody with desired bioactivity. Herein, we developed an intracellular selection method to generate covalent inhibitory antibody against human rhinovirus 14 (HRV14) 3C protease through unnatural amino acid mutagenesis along the heavy chain complementarity-determining region 3 (CDR-H3). A library of antibody mutants was thus constructed and screened in vivo through co-expression with the target protease. Using this screening strategy, six covalent antibodies with proximity-enabled bioactivity were identified, which were shown to covalently target HRV14-3C protease with high inhibitory potency and exquisite selectivity . Compared to structure-based rational design, this library-based screening method provides a simple and efficient way for the discovery and engineering of covalent antibody for enzyme inhibition.
研究领域:
药物发现
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蛋白质工程
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病毒学
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分子生物学
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DOI
PubMed
高影响因子
Cardiovascular Therapeutics
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2026
·Vol. 2026
·期 1
·8444915
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IF 2.8
Weijun Li,Zhenyu Zhao,Xuefeng Lin,Guoliang Chen,Lin Li,Ge Fang,Zhixi Hu
Objective This study is aimed at evaluating the effects of Zhenwu Decoction (ZWD) on cardiac dysfunction, water-retention–related phenotypes, and brain and kidney injury in rats with doxorubicin-induced chronic heart failure (CHF), and at examining whether these effects were accompanied by changes in AVP, V2R, PKA-C α , and AQP2-related markers. Methods Rats that met the prespecified CHF criteria after doxorubicin administration were rerandomized to the model, ZWD-L, ZWD-M, ZWD-H, or tolvaptan groups and treated once daily for 14 consecutive days. Cardiac function, biochemical and water balance–related outcomes, histopathology, brain AVP, and renal V2R, PKA-C α , and AQP2 expression were assessed. The animal was the experimental unit, and the number analyzed is reported for each outcome. Results Compared with the control group, model rats showed impaired cardiac function; increased ascites and tissue water retention; reduced 24-h urine output; histological injury in the heart, brain, and kidney; and altered AVP, V2R, PKA-C α , and AQP2-related markers. ZWD treatment was associated with improvement in these measured outcomes, with the magnitude and statistical support varying across doses. Tolvaptan produced the expected aquaretic reference response. Adjusted p values and the number of animals analyzed are reported for each outcome. Conclusion In this doxorubicin-induced CHF model, ZWD improved cardiac function and water-retention–related phenotypes and was accompanied by changes in AVP, V2R, PKA-C α , and AQP2-related markers. These data support an association but do not establish pathway mediation, direct target engagement, or heart–brain–kidney crosstalk.
✓ 已验证
DOI
高影响因子
Acta Pharmaceutica Sinica B
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2024
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IF 14.7
Yutian Lei,Yuan Shen,Feng Chen,Rui He,Zhang Zhang,Ying Zhou,Jin-Chen Yu,Jacques Crommen,Zhengjin Jiang,Qiqin Wang
The dynamic tracking of antibody‒drug conjugates (ADCs) in serum is crucial. However, a versatile bioanalytical platform is lacking due to serious matrix interferences, the heterogeneity and complex biotransformation of ADCs, and the recognition deficiencies of traditional affinity technologies. To overcome this, a multiepitope recognition technology (MERT) was developed by simultaneously immobilizing CDR and non-CDR ligands onto MOF@AuNPs. MERT’s excellent specificity, ultrahigh ligand density, and potential synergistic recognition ability enable it to target the different key regions of ADCs to overcome the deficiencies of traditional technologies. The binding capacity of MERT for antibodies is ten to hundred times higher than that of the mono-epitope or Fc-specific affinity technologies. Since MERT can efficiently capture target ADCs from serum, a novel bioanalytical platform based on MERT and RPLC‒QTOF-MS has been developed to monitor the dynamic changes of ADCs in serum, including the fast changes of drug-to-antibody ratio from 3.67 to 0.22, the loss of payloads (maytansinol), and the unexpected hydrolysis of the succinimide ring of the linker, which will contribute to clarify the fate of ADCs and provide a theoretical basis for future design. In summary, the MERT-based versatile platform will open a new avenue for in-depth studies of ADCs in biological fluids.
研究领域:
药学
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生物分析化学
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生物技术
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
Biomaterials Advances
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2022
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IF 0
Xuehui Zhang,Yanqin Wang,Xiaogang Wu,Fengbo Zhu,Yi-Xian Qin,Weiyi Chen,Qiang Zheng
The development of biomimetic materials with anisotropic topological structure and wide range of adjustable mechanical properties is central to tissue engineering fields. In this work, on the basis of a stiff/stretchable dually crosslinked hydrogel, we paid more attention to the synergistic contribution of the confined drying and re-swelling (CDR) effect and Hofmeister effect to its micro structures, polymer aggregation states and mechanical strength. Specifically, by changing the pre-strains of the CDR procedure and the soaking time during the salting-out procedure, the arrangement structure orientation, chain-entanglement density, and supramolecular interaction strength within the polymer can be adjusted by changing the processing sequence of the two procedures, so that to obtain anisotropic biomimetic hydrogels with adjustable mechanical properties in a wide range. Thus, this engineered anisotropic polymer can mimic the natural tissues’ mechanical properties in regeneration. Moreover and importantly, these anisotropic hydrogels exhibit prominent self-recovery properties. In summary, with the integration of molecular and structural engineering approaches, this study presents a universal strategy for developing anisotropic hydrogels, which could be widely used as biomimetic substitutes with anisotropic features in tissue regeneration.
研究领域:
材料科学
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组织工程
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
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