We designed a disulfide-crosslinked mini-protein with a two-helical topology consisting of L-and Damino acids,which was exceptionally stable in serum.Therefore,we further used it as a scaffold to design mini-proteins ...We designed a disulfide-crosslinked mini-protein with a two-helical topology consisting of L-and Damino acids,which was exceptionally stable in serum.Therefore,we further used it as a scaffold to design mini-proteins targeting p53 positive tumor cells.Based on bifunctional grafting,key residues from the transactivation domain of p53 and a designed unnatural amino acid were grafted into the helix constituted by L-amino acids to confer the mini-protein with MDM2 inhibitory activity.Meanwhile,ten Arg residues were introduced to improve its membrane penetrating capacity.Among the mini-proteins,UPROL-10e showed nano-molar binding affinity on MDM2 and cellular toxicity on p53 expressing HCT116cells.展开更多
Antitumor drug therapy plays a very important role in cancer treatment.However,resistance to chemotherapy is a serious issue.Many studies have been conducted to understand and verify the cause of chemoresistance from ...Antitumor drug therapy plays a very important role in cancer treatment.However,resistance to chemotherapy is a serious issue.Many studies have been conducted to understand and verify the cause of chemoresistance from multiple points of view such as oncogenes,tumor suppressor genes,DNA mutations and repairs,autophagy,cancer stemness,and mitochondrial metabolism and alteration.Nowadays,not only medical data from hospitals but also public big data exist on internet websites.Consequently,the importance of computational science has vastly increased in biological and medical sciences.Using statistical or mathematical analyses of these medical data with conventional experiments,many researchers have recently shown that there is a strong relationship between the biological metabolism and chemoresistance for cancer therapy.For example,folate metabolism that mediates one-carbon metabolism and polyamine metabolism have garnered attention regarding their association with cancer.It has been suggested that these metabolisms may be involved in causing resistance to chemotherapy.展开更多
基金supported by the National Natural Science Foundation of China(Nos.3217110331 and 8212200560)Major new drug development in Shandong Province(No.2020CXGC010503)。
文摘We designed a disulfide-crosslinked mini-protein with a two-helical topology consisting of L-and Damino acids,which was exceptionally stable in serum.Therefore,we further used it as a scaffold to design mini-proteins targeting p53 positive tumor cells.Based on bifunctional grafting,key residues from the transactivation domain of p53 and a designed unnatural amino acid were grafted into the helix constituted by L-amino acids to confer the mini-protein with MDM2 inhibitory activity.Meanwhile,ten Arg residues were introduced to improve its membrane penetrating capacity.Among the mini-proteins,UPROL-10e showed nano-molar binding affinity on MDM2 and cellular toxicity on p53 expressing HCT116cells.
基金Our research group was funded by Taiho Pharmaceutical Co.,Ltd.(Tokyo,Japan),UNITECH Co.,Ltd.(Chiba,Japan),IDEA Consultants Inc.(Tokyo,Japan),Kinshu-kai Medical Corporation(Osaka,Japan).
文摘Antitumor drug therapy plays a very important role in cancer treatment.However,resistance to chemotherapy is a serious issue.Many studies have been conducted to understand and verify the cause of chemoresistance from multiple points of view such as oncogenes,tumor suppressor genes,DNA mutations and repairs,autophagy,cancer stemness,and mitochondrial metabolism and alteration.Nowadays,not only medical data from hospitals but also public big data exist on internet websites.Consequently,the importance of computational science has vastly increased in biological and medical sciences.Using statistical or mathematical analyses of these medical data with conventional experiments,many researchers have recently shown that there is a strong relationship between the biological metabolism and chemoresistance for cancer therapy.For example,folate metabolism that mediates one-carbon metabolism and polyamine metabolism have garnered attention regarding their association with cancer.It has been suggested that these metabolisms may be involved in causing resistance to chemotherapy.
