药学学报, 2017, 52(9): 1379-1386
引用本文:
杨旭, 张翔. 分枝杆菌膜蛋白3抑制剂的研究进展[J]. 药学学报, 2017, 52(9): 1379-1386.
YANG Xu, ZHANG Xiang. Recent advances in study of mycobacterial membrane protein large 3 inhibitors[J]. Acta Pharmaceutica Sinica, 2017, 52(9): 1379-1386.

分枝杆菌膜蛋白3抑制剂的研究进展
杨旭, 张翔
中国医学科学院、北京协和医学院药物研究所, 活性物质发现与适药化研究北京市重点实验室, 北京 100050
摘要:
分枝杆菌膜蛋白3(mycobacterial membrane protein large 3,MmpL3)属于抗瘤细胞分裂(RND)蛋白超家族,它主要参与结核分枝杆菌中海藻糖单霉菌酸酯的转运过程,对MmpL3的抑制可以影响结核分枝杆菌细胞壁的合成。近年来,通过表型筛选已发现并确证了7类不同化学骨架的MmpL3抑制剂,拟用于耐药结核病的治疗。本文将简要论述这几类MmpL3抑制剂及其构效关系,介绍靶标确证的方法,并进一步探讨MmpL3抑制剂的作用机制。
关键词:    分枝杆菌膜蛋白3      结核分枝杆菌      构效关系      作用机制     
Recent advances in study of mycobacterial membrane protein large 3 inhibitors
YANG Xu, ZHANG Xiang
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China
Abstract:
Mycobacterial membrane protein large 3 (MmpL3) belongs to the resistance, nodulation and division (RND) superfamily whose role in mycobacteria is transporting trehalosemonomycolate (TMM). The inhibition of MmpL3 influences the formation of cell wall of mycobacteria. In the past few years, several whole cell-based screenings of compound libraries by different research groups has brought by a number of diverse chemical scaffolds active against Mycobacterium tuberculosis (Mtb). The aim of this review is to provide the recent advances in discovery of MmpL3 inhibitors with a special focus on the structure-activity relationship (SAR). Besides, this review will provide the information of target identification and the modes of action of the MmpL3 inhibitors.
Key words:    mycobacterial membrane protein large 3    Mycobacterium tuberculosis    structure-activity relationship    modes of action   
收稿日期: 2017-01-16
DOI: 10.16438/j.0513-4870.2017-0058
基金项目: 国家科技重大专项"重大新药创制"子课题2015ZX09102007"抗耐药结核新药TBI-001的临床前研究".
通讯作者: 张翔,Tel:86-10-63165248,E-mail:simon@imm.ac.cn
Email: simon@imm.ac.cn
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参考文献:
[1] Global tuberculosis report 2015[M]. 20th ed. World Health Organization, 2015:1-3.
[2] Cooper CB. Development of Mycobacterium tuberculosis whole cell screening hits as potential antituberculosis agents:miniperspectives series on phenotypic screening for antiinfective targets[J]. J Med Chem, 2013, 56:7755-7760.
[3] Quy H, Lönnroth K, Lan N, et al. Treatment results among tuberculosis patients treated by private lung specialists involved in a public-private mix project in Vietnam[J]. Int J Tuberc Lung Dis, 2003, 7:1139-1146.
[4] Goldberg DE, Siliciano RF, Jacobs WR. Outwitting evolution:fighting drug-resistant TB, malaria, and HIV[J]. Cell, 2012, 148:1271-1283.
[5] Zumla A, Abubakar I, Raviglione M, et al. Drug-resistant tuberculosis-current dilemmas, unanswered questions, challenges, and priority needs[J]. J Infect Dis, 2012, 205(suppl 2):S228-S240.
[6] Rivers EC, Mancera RL. New anti-tuberculosis drugs in clinical trials with novel mechanisms of action[J]. Drug Discov Today, 2008, 13:1090-1098.
[7] Lee RE, Protopopova M, Crooks E, et al. Combinatorial lead optimization of[1, 2] -diamines based on ethambutol as potential antituberculosis preclinical candidates[J]. J Comb Chem, 2003, 5:172-187.
[8] Tahlan K, Wilson R, Kastrinsky DB, et al. SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis[J]. Antimicrob Agents Chem, 2012, 56:1797-1809.
[9] Sacksteder KA, Protopopova M, Barry CE, et al. Discovery and development of SQ109:a new antitubercular drug with a novel mechanism of action[J]. Future Microbiol, 2012, 7:823-837.
[10] Poce G, Consalvi S, Biava M. MmpL3 inhibitors:diverse chemical scaffolds inhibit the same target[J]. Mini Rev Med Chem, 2016, 16:1274-1283.
[11] Bogatcheva E, Hanrahan C, Nikonenko B, et al. Identification of SQ609 as a lead compound from a library of dipiperidines[J]. Bioorg Med Chem Lett, 2011, 21:5353-5357.
[12] Li K, Schurig-Briccio LA, Feng X, et al. Multitarget drug discovery for tuberculosis and other infectious diseases[J]. J Med Chem, 2014, 57:3126-3139.
[13] Collins L, Franzblau SG. Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium[J]. Antimicrob Agents Chem, 1997, 41:1004-1009.
[14] Onajole OK, Pieroni M, Tipparaju SK, et al. Preliminary structure-activity relationships and biological evaluation of novel antitubercular indolecarboxamide derivatives against drugsusceptible and drug-resistant Mycobacterium tuberculosis strains[J]. J Med Chem, 2013, 56:4093-4103.
[15] Kondreddi RR, Jiricek J, Rao SP, et al. Design, synthesis, and biological evaluation of indole-2-carboxamides:a promising class of antituberculosis agents[J]. J Med Chem, 2013, 56:8849-8859.
[16] Stec J, Onajole OK, Lun S, et al. Indole-2-carboxamidebased MmpL3 inhibitors show exceptional antitubercular activity in an animal model of tuberculosis infection[J]. J Med Chem, 2016, 59:6232-6247.
[17] Brown JR, North EJ, Hurdle JG, et al. The structure activity relationship of urea derivatives as anti-tuberculosis agents[J]. Bioorg Med Chem, 2011, 19:5585-5595.
[18] Scherman MS, North EJ, Jones V, et al. Screening a library of 1600 adamantyl ureas for anti-Mycobacterium tuberculosis activity in vitro and for better physical chemical properties for bioavailability[J]. Bioorg Med Chem, 2012, 20:3255-3262.
[19] Deidda D, Lampis G, Fioravanti R, et al. Bactericidal activities of the pyrrole derivative BM212 against multidrugresistant and intramacrophagic Mycobacterium tuberculosis strains[J]. Antimicrob Agents Chem, 1998, 42:3035-3037.
[20] Wang H, Wen H, Cui HQ, et al. Synthesis and anti-tubercular activity of 1-(2-adamantyl)-3-(2,3,4-trifluorophenyl)urea derivatives[J]. Chin J Med Chem(中国药物化学杂志), 2016, 26:280-287.
[21] Remuiñán MJ, Pérez-Herrán E, Rullás J, et al. Tetrahydropyrazolo[1,5-a] pyrimidine-3-carboxamide and N-benzyl-6', 7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] analogues with bactericidal efficacy against Mycobacterium tuberculosis targeting MmpL3[J]. PLoS One, 2013, 8:e60933.
[22] Yokokawa F, Wang G, Chan WL, et al. Discovery of tetrahydropyrazolopyrimidine carboxamide derivatives as potent and orally active antitubercular agents[J]. ACS Med Chem Lett, 2013, 4:451-455.
[23] Poce G, Bates RH, Alfonso S, et al. Improved BM212 MmpL3 inhibitor analogue shows efficacy in acute murine model of tuberculosis infection[J]. PLoS One, 2013, 8:e56980.
[24] Biava M, Porretta GC, Poce G, et al. Antimycobacterial agents. Novel diarylpyrrole derivatives of BM212 endowed with high activity toward Mycobacterium tuberculosis and low cytotoxicity[J]. J Med Chem, 2006, 49:4946-4952.
[25] Biava M, Porretta GC, Poce G, et al. Identification of a novel pyrrole derivative endowed with antimycobacterial activity and protection index comparable to that of the current antitubercular drugs streptomycin and rifampin[J]. Bioorg Med Chem, 2010, 18:8076-8084.
[26] Rullas J, García JI, Beltrán M, et al. Fast standardized therapeutic-efficacy assay for drug discovery against tuberculosis[J]. Antimicrob Agents Chem, 2010, 54:2262-2264.
[27] Stanley SA, Grant SS, Kawate T, et al. Identification of novel inhibitors of M. tuberculosisgrowth using whole cell based high-throughput screening[J]. ACS Chem Biol, 2012, 7:1377-1384.
[28] Stanley SA, Grant SS, Kawate T, et al. Identification of novel inhibitors of M. tuberculosis growth using whole cell based high-throughput screening[J]. ACS Chem Biol, 2012, 7:1377-1384.
[29] Rayasam GV. MmpL3 a potential new target for development of novel anti-tuberculosis drugs[J]. Expert Opin Ther Target, 2014, 18:247-256.
[30] Yamaryo-Botte Y, Rainczuk AK, Lea-Smith DJ, et al. Acetylation of trehalose mycolates is required for efficient MmpLmediated membrane transport in corynebacterineae[J]. ACS Chem Biol, 2014, 10:734-746.
[31] Kaur D, Guerin ME, Škovierová H, et al. Biogenesis of the cell wall and other glycoconjugates of Mycobacterium tuberculosis[J]. Adv Appl Microbiol, 2009, 69:23-78.
[32] Vander Beken S, Al Dulayymi J a R, Naessens T, et al. Molecular structure of the Mycobacterium tuberculosis virulence factor, mycolic acid, determines the elicited inflamematory pattern[J]. Eur J Immunol, 2011, 41:450-460.
[33] Schweizer E, Hofmann J. Microbial type I fatty acid synthases (FAS):major players in a network of cellular FAS systems[J]. Microbiol Mol Biol Rev, 2004, 68:501-517.
[34] Nataraj V, Varela C, Javid A, et al. Mycolic acids:deciphering and targeting the Achilles' heel of the tubercle bacillus[J]. Mol Microbiol, 2015, 98:7-16.
[35] Nobre A, Alarico S, Maranha A, et al. The molecular biology of mycobacterial trehalose in the quest for advanced tuberculosis therapies[J]. Microbiology, 2014, 160:1547-1570.
[36] Varela C, Rittmann D, Singh A, et al. MmpL genes are associated with mycolic acid metabolism in mycobacteria and corynebacteria[J]. Chem Biol, 2012, 19:498-506.
[37] Belardinelli JM, Yazidi A, Yang L, et al. Structure-function profile of MmpL3, the essential mycolic acid transporter from Mycobacterium tuberculosis[J]. ACS Infect Dis, 2016, 2:702-713.
[38] Domenech P, Reed MB, Barry CE. Contribution of the Mycobacterium tuberculosis MmpL protein family to virulence and drug resistance[J]. Infect Immun, 2005, 73:3492-3501.
[39] Goldman RC. Why are membrane targets discovered by phenotypic screens and genome sequencing in Mycobacterium tuberculosis?[J]. Tuberculosis, 2013, 93:569-588.
[40] Li W, Upadhyay A, Fontes FL, et al. Novel insights into the mechanism of inhibition of MmpL3, a target of multiple pharmacophores in Mycobacterium tuberculosis[J]. Antimicrob Agents Chem, 2014, 58:6413-6423.
[41] Lun S, Guo H, Onajole OK, et al. Indoleamides are active against drug-resistant Mycobacterium tuberculosis[J]. Nat Commun, 2013, 4:2907.
[42] Grzegorzewicz AE, Pham H, Gundi VA, et al. Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane[J]. Nat Chem Biol, 2012, 8:334-341.
[43] Foss MH, Pou S, Davidson PM, et al. Diphenylethermodified 1, 2-diamines with improved drug properties for development against Mycobacterium tuberculosis[J]. ACS Infect Dis, 2016, 2:500-508.
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