Intramolecular Interactions Enhance the Potency of Gallinamide A Analogues against Trypanosoma cruzi

被引:17
作者
Da Silva, Elany Barbosa [1 ]
Sharma, Vandna [1 ]
Hernandez-Alvarez, Lilian [1 ,2 ]
Tang, Arthur H. [3 ,4 ]
Stoye, Alexander [3 ,4 ]
O'Donoghue, Anthony J. [1 ]
Gerwick, William H. [1 ,5 ]
Payne, Richard J. [3 ,4 ]
McKerrow, James H. [1 ]
Podust, Larissa M. [1 ]
机构
[1] Univ Calif San Diego, Ctr Discovery & Innovat Parasit Dis, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA
[2] Univ Estadual Paulista, Inst Biociencias Letras & Ciencias Exatas, Dept Fis, BR-15054000 Sao Paulo, Brazil
[3] Univ Sydney, Sch Chem, Sydney, NSW 2006, Australia
[4] Univ Sydney, Australian Res Council, Ctr Excellence Innovat Peptide & Prot Sci, Sydney, NSW 2006, Australia
[5] Univ Calif San Diego, Ctr Marine Biotechnol & Biomed, Scripps Inst Oceanog, La Jolla, CA 92093 USA
基金
巴西圣保罗研究基金会; 英国医学研究理事会;
关键词
CYSTEINE PROTEASE CRUZAIN; FREE-ENERGY DECOMPOSITION; CHAGAS-DISEASE; STRUCTURAL DETERMINANTS; ANTIMALARIAL ACTIVITY; MOLECULAR-DYNAMICS; INHIBITORS; BINDING; BURDEN; PROTEINASE;
D O I
10.1021/acs.jmedchem.1c02063
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Gallinamide A, a metabolite of the marine cyanobacterium Schizothrix sp., selectively inhibits cathepsin L-like cysteine proteases. We evaluated the potency of gallinamide A and 23 synthetic analogues against intracellular Trypanosoma cruzi amastigotes and the cysteine protease, cruzain. We determined the co-crystal structures of cruzain with gallinamide A and two synthetic analogues at similar to 2 angstrom angstrom. SAR data revealed that the N-terminal end of gallinamide A is loosely bound and weakly contributes in drug-target interactions. At the C-terminus, the intramolecular pi-pi stacking interactions between the aromatic substituents at P1' and P1 restrict the bioactive conformation of the inhibitors, thus minimizing the entropic loss associated with target binding. Molecular dynamics simulations showed that in the absence of an aromatic group at P1, the substituent at P1' interacts with tryptophan-184. The P1-P1' interactions had no effect on anti-cruzain activity, whereas anti-T. cruzi potency increased by similar to fivefold, likely due to an increase in solubility/permeability of the analogues.
引用
收藏
页码:4255 / 4269
页数:15
相关论文
共 73 条
[1]  
[Anonymous], 2015, NONLINEAR REGRESSION
[2]   Potent Anti-SARS-CoV-2 Activity by the Natural Product Gallinamide A and Analogues via Inhibition of Cathepsin L [J].
Ashhurst, Anneliese S. ;
Tang, Arthur H. ;
Fajtova, Pavla ;
Yoon, Michael C. ;
Aggarwal, Anupriya ;
Bedding, Max J. ;
Stoye, Alexander ;
Beretta, Laura ;
Pwee, Dustin ;
Drelich, Aleksandra ;
Skinner, Danielle ;
Li, Linfeng ;
Meek, Thomas D. ;
McKerrow, James H. ;
Hook, Vivian ;
Tseng, Chien-Te ;
Larance, Mark ;
Turville, Stuart ;
Gerwick, William H. ;
O'Donoghue, Anthony J. ;
Payne, Richard J. .
JOURNAL OF MEDICINAL CHEMISTRY, 2022, 65 (04) :2956-2970
[3]   THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].
BAILEY, S .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :760-763
[4]   Chemical Characterization and Trypanocidal, Leishmanicidal and Cytotoxicity Potential of Lantana camara L. (Verbenaceae) Essential Oil [J].
Barros, Luiz Marivando ;
Duarte, Antonia Eliene ;
Morais-Braga, Maria Flaviana Bezerra ;
Waczuk, Emily Pansera ;
Vega, Celeste ;
Leite, Nadghia Figueiredo ;
Alencar de Menezes, Irwin Rose ;
Melo Coutinho, Henrique Douglas ;
Teixeira Rocha, Joao Batista ;
Kamdem, Jean Paul .
MOLECULES, 2016, 21 (02)
[5]   MOLECULAR-DYNAMICS WITH COUPLING TO AN EXTERNAL BATH [J].
BERENDSEN, HJC ;
POSTMA, JPM ;
VANGUNSTEREN, WF ;
DINOLA, A ;
HAAK, JR .
JOURNAL OF CHEMICAL PHYSICS, 1984, 81 (08) :3684-3690
[6]   Current drug therapy and pharmaceutical challenges for Chagas disease [J].
Bermudez, Jose ;
Davies, Carolina ;
Simonazzi, Analia ;
Pablo Real, Juan ;
Palma, Santiago .
ACTA TROPICA, 2016, 156 :1-16
[7]   ATOMIC CHARGES DERIVED FROM SEMIEMPIRICAL METHODS [J].
BESLER, BH ;
MERZ, KM ;
KOLLMAN, PA .
JOURNAL OF COMPUTATIONAL CHEMISTRY, 1990, 11 (04) :431-439
[8]   SUBCELLULAR-LOCALIZATION OF A CYSTEINE PROTEINASE FROM TRYPANOSOMA-CRUZI [J].
BONTEMPI, E ;
MARTINEZ, J ;
CAZZULO, JJ .
MOLECULAR AND BIOCHEMICAL PARASITOLOGY, 1989, 33 (01) :43-48
[9]   Design of Gallinamide A Analogs as Potent Inhibitors of the Cysteine Proteases Human Cathepsin L and Trypanosoma cruzi Cruzain [J].
Boudreau, Paul D. ;
Miller, Bailey W. ;
McCall, Laura-Isobel ;
Almaliti, Jehad ;
Reher, Raphael ;
Hirata, Ken ;
Le, Thu ;
Siqueira-Neto, Jair L. ;
Hook, Vivian ;
Gerwick, William H. .
JOURNAL OF MEDICINAL CHEMISTRY, 2019, 62 (20) :9026-9044
[10]   A target within the target:: probing Cruzain's P1′ site to define structural determinants for the Chagas' disease protease [J].
Brinen, LS ;
Hansell, E ;
Cheng, JM ;
Roush, WR ;
McKerrow, JH ;
Fletterick, RJ .
STRUCTURE WITH FOLDING & DESIGN, 2000, 8 (08) :831-840