基于抗Pgp单抗的药物设计

Development of drug resistance in tumors during treatment is a major factor limiting the clinical use of anticancer agents. Overexpression of P-glycoprotein has been associated with MDR in some cancer cells undergoing chemotherapy. We have prepared monoclonal antibody (PHMA02) which is directed against an external epitope of P-glycoprotein. A single chain variable domain construct of PHMA02 was made, expressed in E. Coli, and its specific for Pgp represents a significant advance in target therapy for Pgp-expressing tumor cells. From the three dementional structure analysis of computer modeling of PHMA02 CDR loops, we have used a structure-based approach to design a small peptide mimetic. Flow cytometry showed the anti-Pgp peptide mimetic functionally similar to PHMA02. The peptide mimetic competitively inhibits PHMA02 binding to Pgp and partially block the Pgp function as a drug efflux pump in K562/A02 cells. Some special conformational properties of CDR loops of antibody might serve as lead structures for develop new biological peptide mimetics. The general principles derived from the design of small pharmacological agents based on the structural features of antibodies would accelerate drug development.

基于抗体的新药设计是免疫学、分子生物学与药物化学界面上开展工作，起点以与P糖蛋白匾煨越岷系目筆gp单抗为模板，通过随机突变法结合定点突变法，运用计算机辅助设计方法构建并合成出肽类或模拟肽类小分子，确定1～2类与Pgp靶点特异性结合的高亲和力或具有鸵┠孀饔玫南鹊蓟衔铮罢倚乱┨剿饕惶跣碌挠行揪丁

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