33900-18-4Relevant articles and documents
Mapping the s1 and s1’ subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents
Cianni, Lorenzo,Lemke, Carina,Gilberg, Erik,Feldmann, Christian,Rosini, Fabiana,Rocho, Fernanda Dos Reis,Ribeiro, Jean F. R.,Tezuka, Daiane Y.,Lopes, Carla D.,de Albuquerque, Sérgio,Bajorath, Jürgen,Laufer, Stefan,Leit?o, Andrei,Gütschow, Michael,Montanariid, Carlos A.
, (2020/04/24)
The cysteine protease cruzipain is considered to be a validated target for therapeutic intervention in the treatment of Chagas disease. A series of 26 new compounds were designed, synthesized, and tested against the recombinant cruzain (Cz) to map its S1/S1′ subsites. The same series was evaluated on a panel of four human cysteine proteases (CatB, CatK, CatL, CatS) and Leishmania mexicana CPB, which is a potential target for the treatment of cutaneous leishmaniasis. The synthesized compounds are dipeptidyl nitriles designed based on the most promising combinations of different moieties in P1 (ten), P2 (six), and P3 (four different building blocks). Eight compounds exhibited a Ki smaller than 20.0 nM for Cz, whereas three compounds met these criteria for LmCPB. Three inhibitors had an EC50 value of ca. 4.0 μM, thus being equipotent to benznidazole according to the antitrypanosomal effects. Our mapping approach and the respective structure-activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cysteine proteases.
Structure-activity study of endomorphin-2 analogs with C-terminal modifications by NMR spectroscopy and molecular modeling
Wang, Chang-lin,Yao, Jin-long,Yu, Ye,Shao, Xuan,Cui, Yun,Liu, Hong-mei,Lai, Lu-hao,Wang, Rui
, p. 6415 - 6422 (2008/12/21)
Endomorphin-2 (EM-2) is a putative endogenous μ-opioid receptor ligand. To get insight into the important role of C-terminal amide group of EM-2, we investigated herein a series of EM-2 analogs by substitution of the C-terminal amide group with -NHNH2, -NHCH3, -N(CH3)2, -OCH3, -OCH2CH3, -OC(CH3)3, and -CH2-OH. Their binding affinity and bioactivity were determined and compared. Despite similar (analogs 1, 4, and 7) or decreased (analogs 2, 3,5, and 6) μ affinity in binding assays, all analogs showed low guinea pig ileum (GPI) and mouse vas deferens (MVD) potencies compared to their parent peptide. Interestingly, as for analogs 2 and 3 (a single and double N-methylation of C-terminal amide), the potency order with the Ki (μ) values was 2 > 3; for the C-terminal esterified analogs 4-6, the potency order with the Ki (μ) values was 4 > 5 > 6. Thus, we concluded that the steric hindrance of C-terminus might play an important role in opioid receptor affinity. We further investigated the conformational properties of these analogs by 1D and 2D 1H NMR spectroscopy and molecular modeling. Evaluating the ratios of cis- and trans-isomers, aromatic interactions, dihedral angles, and stereoscopic views of the most convergent conformers, we found that modifications at the C-terminal amide group of EM-2 affected these analog conformations markedly, therefore changed the opioid receptor affinity and in vitro bioactivity.
Structural studies of [2′,6′-dimethyl-L-tyrosine1]endomorphin-2 analogues: Enhanced activity and cis orientation of the Dmt-Pro amide bond
Okada, Yoshio,Fujita, Yoshio,Motoyama, Takashi,Tsuda, Yuko,Yokoi, Toshio,Li, Tingyou,Sasaki, Yusuke,Ambo, Akihiro,Jinsmaa, Yunden,Bryant, Sharon D.,Lazarus, Lawrence H.
, p. 1983 - 1994 (2007/10/03)
Analogues of endomorphin-2 (EM-2: Tyr-Pro-Phe-Phe-NH2) (1) were designed to examine the importance of each residue on μ-opioid receptor interaction. Replacement of Tyr1 by 2′,6′-dimethyl-L-tyrosine (Dmt) (9-12) exerted profound effects: [Dmt1]EM-2 (9) elevated μ-opioid affinity 4.6-fold (Kiμ=0.15 nM) yet selectivity fell 330-fold as δ-affinity rose (Kiδ=28.2 nM). This simultaneous increased μ- and δ-receptor bioactivities resulted in dual agonism (IC50=0.07 and 1.87 nM, respectively). While substitution of Phe4 by a phenethyl group (4) decreased μ affinity (Kiμ=13.3 nM), the same derivative containing Dmt (12) was comparable to EM-2 but also acquired weak δ antagonism (pA2=7.05). 1H NMR spectroscopy revealed a trans configuration (1:2 to 1:3, cis/trans) in the Tyr-Pro amide bond, but a cis configuration (5:3 to 13:7, cis/trans) with Dmt-Pro analogues.
