Inhibition of Human and Yeast 20S Proteasome by Analogues of Trypsin Inhibitor SFTI-1

Abstract

Starting from the primary structure of sunflower trypsin inhibitor SFTI-1, we designed novel non-covalent inhibitors of human and yeast 20S proteasomes. Peptides with Arg residue in P1 position and two basic amino acid residues (Lys or/and Arg) in P2′ and P3′ positions strongly inhibited chymotrypsin-like and caspase-like activities, while trypsin-like activity was poorly modified. We found that some SFTI-1 analogues up-regulated exclusively the chymotrypsin-like activity of latent yeast 20S proteasome.

Noncovalent inhibitors of human 20S and 26S proteasome based on trypsin inhibitor SFTI‐1

“…Recently, we have introduced a set of novel non‐covalent in vitro inhibitors of yeast and human 20S proteasomes . Their primary structures were designed based on the sunflower‐derived trypsin inhibitor SFTI‐1 (Figure ) .…”

“… Primary structures of wild‐type SFTI‐1 (A), and its monocyclic analogue [Arg,Lys]SFTI‐1 (B) which inhibits yeast and human 20S proteasome …”

Inhibition of human constitutive 20S proteasome and 20S immunoproteasome with novel N‐terminally modified peptide aldehydes and their antitumor activity

“…All of them have a hydrophilic polyethylene glycol derivative, 8‐amino‐3,6‐dioxaoctanoyl group (O2Octa) attached to their N ‐terminal amino groups. This derivative was used in our previous research on noncovalent proteasome inhibitors, which were designed based on the primary structure of peptidic sunflower trypsin inhibitor SFTI‐1 …”

Prospects for the design of new therapeutically significant protease inhibitors based on knottins and sunflower seed trypsin inhibitor (SFTI 1)

“…В организме существует много сериновых протеаз, и важно обеспечить селективное воздействие на тот фермент, который отвечает за развитие патологии. Известно также, что некоторые аналоги SFTI 1 могут воздействовать и на цистеиновые протеазы протеасом [139]. Пока нет ответов на вопросы, достаточно ли компьютерного моделирования для оценки селективности взаимодействия ингибитора с целевым ферментом; каковы критерии селективности, например, достаточно ли разницы в величинах K i одним и тем же ингибитором матриптазы 2 и матриптазы 1 в 15 раз [140] для селективного торможения одного из двух ферментов; сколько и каких ферментов надо тестировать на взаимодействие с новым ингибитором, чтобы доказать его селективность.…”