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摘要
治疗阿尔茨海默氏症可能不会有“灵丹妙药”;相反,我们应该追求一种“神奇的猎枪爆炸”,以多种互补的治疗受体为目标。虽然蛋白质错误折叠/寡聚化可能是这些靶标之一,但仅靠这一点是不够的,还需要其他治疗实体共同给药,如免疫病变、胶质病、线粒体病、突触毒性或其他靶标。虽然多种药物治疗正在成为首选的治疗途径,但许多问题仍未得到解答。这应该是一种生物制剂的鸡尾酒,一种小分子的混合物,还是两者的明智组合?生物制剂和小分子药物各有优缺点。在解决像阿尔茨海默病这样复杂且具有全球重要性的疾病时,这两种治疗方法都应该有继续发展的空间。每一种都有很多可以提供的东西,当明确地使用它们的优点和缺点时,最终的解决方案可能需要两者的贡献。
关键词: 阿尔茨海默病,药物设计,生物制剂,小分子药物,免疫病变,寡聚化。
[1]
Li, X.; Feng, X.; Sun, X.; Hou, N.; Han, F.; Liu, Y. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990–2019. Front. Aging Neurosci., 2022, 14, 937486.
[http://dx.doi.org/10.3389/fnagi.2022.937486] [PMID: 36299608]
[http://dx.doi.org/10.3389/fnagi.2022.937486] [PMID: 36299608]
[2]
Ramanan, V.K.; Day, G.S. Anti-amyloid therapies for Alzheimer disease: Finally, good news for patients. Mol. Neurodegener., 2023, 18(1), 42.
[http://dx.doi.org/10.1186/s13024-023-00637-0] [PMID: 37381015]
[http://dx.doi.org/10.1186/s13024-023-00637-0] [PMID: 37381015]
[3]
Kurkinen, M.T. Donanemab: Not two without a third. Adv. Clin. Exp. Med., 2023, 32(10), 1085-1087.
[http://dx.doi.org/10.17219/acem/172673] [PMID: 37831471]
[http://dx.doi.org/10.17219/acem/172673] [PMID: 37831471]
[4]
Doytchinova, I. Drug design—past, present, future. Molecules, 2022, 27(5), 1496.
[http://dx.doi.org/10.3390/molecules27051496] [PMID: 35268598]
[http://dx.doi.org/10.3390/molecules27051496] [PMID: 35268598]
[5]
Hughes, J.P.; Rees, S.; Kalindjian, S.B.; Philpott, K.L. Principles of early drug discovery. Br. J. Pharmacol., 2011, 162(6), 1239-1249.
[http://dx.doi.org/10.1111/j.1476-5381.2010.01127.x] [PMID: 21091654]
[http://dx.doi.org/10.1111/j.1476-5381.2010.01127.x] [PMID: 21091654]
[6]
Biala, G.; Kedzierska, E.; Slomka, K.M.; Gorka, O.J.; Hmaidan, S.; Skrok, A.; Kaminski, J.; Havrankova, E.; Nadaska, D.; Malik, I. Research in the field of drug design and development. Pharmaceuticals, 2023, 16(9), 1283.
[http://dx.doi.org/10.3390/ph16091283] [PMID: 37765091]
[http://dx.doi.org/10.3390/ph16091283] [PMID: 37765091]
[7]
Chan, J.C.N.; Chan, A.T.C. Biologics and biosimilars: What, why and how? ESMO Open, 2017, 2(1), e000180.
[http://dx.doi.org/10.1136/esmoopen-2017-000180]
[http://dx.doi.org/10.1136/esmoopen-2017-000180]
[8]
Morrow, T.; Felcone, L.H. Defining the difference: What makes biologics unique. Biotechnol. Healthc., 2004, 1(4), 24-29.
[PMID: 23393437]
[PMID: 23393437]
[9]
Rader, R.A. (Re)defining biopharmaceutical. Nat. Biotechnol., 2008, 26(7), 743-751.
[http://dx.doi.org/10.1038/nbt0708-743] [PMID: 18612293]
[http://dx.doi.org/10.1038/nbt0708-743] [PMID: 18612293]
[10]
Adami, G; Saag, KG; Chapurlat, RD Balancing benefits and risks in the era of biologics. Ther. Adv. Musculoskelet. Dis., 2019, 11, 1759720X19883973.
[http://dx.doi.org/10.1177/1759720X19883973]
[http://dx.doi.org/10.1177/1759720X19883973]
[11]
Chen, B.K.; Yang, Y.T.; Bennett, C.L. Why biologics and biosimilars remain so expensive: Despite two wins for biosimilars, the supreme court’s recent rulings do not solve fundamental barriers to competition. Drugs, 2018, 78(17), 1777-1781.
[http://dx.doi.org/10.1007/s40265-018-1009-0] [PMID: 30446980]
[http://dx.doi.org/10.1007/s40265-018-1009-0] [PMID: 30446980]
[12]
Yu, Y.B.; Briggs, K.T.; Taraban, M.B.; Brinson, R.G.; Marino, J.P. Grand challenges in pharmaceutical research series: Ridding the cold chain for biologics. Pharm. Res., 2021, 38(1), 3-7.
[http://dx.doi.org/10.1007/s11095-021-03008-w] [PMID: 33555493]
[http://dx.doi.org/10.1007/s11095-021-03008-w] [PMID: 33555493]
[13]
Su, Z.; Wang, B.; Almo, S.C.; Wu, Y. Understanding the targeting mechanisms of multi-specific biologics in immunotherapy with multiscale modeling. iScience, 2020, 23(12), 101835.
[http://dx.doi.org/10.1016/j.isci.2020.101835] [PMID: 33305190]
[http://dx.doi.org/10.1016/j.isci.2020.101835] [PMID: 33305190]
[14]
Singh, J.A.; Wells, G.A.; Christensen, R.; Ghogomu, T.E.; Maxwell, L.J.; MacDonald, J.K.; Filippini, G.; Skoetz, N.; Francis, D.K.; Lopes, L.C.; Guyatt, G.H.; Schmitt, J.; La Mantia, L.; Weberschock, T.; Roos, J.F.; Siebert, H.; Hershan, S.; Cameron, C.; Lunn, M.P.T.; Tugwell, P.; Buchbinder, R. Adverse effects of biologics: A network meta-analysis and Cochrane overview. Cochrane Libr., 2011, 2016(4), CD008794.
[http://dx.doi.org/10.1002/14651858.CD008794.pub2] [PMID: 21328309]
[http://dx.doi.org/10.1002/14651858.CD008794.pub2] [PMID: 21328309]
[15]
Joseph, D; Tintinger, GR; Ker, JA; Pannell, N Adverse effects of biologic anti-inflammatory agents on the respiratory system: A review. Afr. J. Thorac. Crit. Care Med., 2021, 27(2), 10.7196/AJTCCM.2021.v27i2.117.
[http://dx.doi.org/10.7196/AJTCCM.2021.v27i2.117]
[http://dx.doi.org/10.7196/AJTCCM.2021.v27i2.117]
[16]
Clarke, J.B. Mechanisms of adverse drug reactions to biologics. Handb. Exp. Pharmacol., 2010, 196(196), 453-474.
[http://dx.doi.org/10.1007/978-3-642-00663-0_16] [PMID: 20020272]
[http://dx.doi.org/10.1007/978-3-642-00663-0_16] [PMID: 20020272]
[17]
Pardridge, W.M. Delivery of biologics across the blood–brain barrier with molecular trojan horse technology. BioDrugs, 2017, 31(6), 503-519.
[http://dx.doi.org/10.1007/s40259-017-0248-z] [PMID: 29067674]
[http://dx.doi.org/10.1007/s40259-017-0248-z] [PMID: 29067674]
[18]
Lajoie, J.M.; Shusta, E.V. Targeting receptor-mediated transport for delivery of biologics across the blood-brain barrier. Annu. Rev. Pharmacol. Toxicol., 2015, 55(1), 613-631.
[http://dx.doi.org/10.1146/annurev-pharmtox-010814-124852] [PMID: 25340933]
[http://dx.doi.org/10.1146/annurev-pharmtox-010814-124852] [PMID: 25340933]
[19]
Rahman, A.; Hossen, M.A.; Chowdhury, M.F.I.; Bari, S.; Tamanna, N.; Sultana, S.S.; Haque, S.N.; Al Masud, A.; Rahman, S.U.K.M. Aducanumab for the treatment of Alzheimer’s disease: A systematic review. Psychogeriatrics, 2023, 23(3), 512-522.
[http://dx.doi.org/10.1111/psyg.12944] [PMID: 36775284]
[http://dx.doi.org/10.1111/psyg.12944] [PMID: 36775284]
[20]
Beshir, S.A.; Aadithsoorya, A.M.; Parveen, A.; Goh, S.S.L.; Hussain, N.; Menon, V.B. Aducanumab therapy to treat alzheimer’s disease: A narrative review. Int. J. Alzheimers Dis., 2022, 2022, 1-10.
[http://dx.doi.org/10.1155/2022/9343514] [PMID: 35308835]
[http://dx.doi.org/10.1155/2022/9343514] [PMID: 35308835]
[21]
Lannfelt, L.; Möller, C.; Basun, H.; Osswald, G.; Sehlin, D.; Satlin, A.; Logovinsky, V.; Gellerfors, P. Perspectives on future Alzheimer therapies: Amyloid-β protofibrils - A new target for immunotherapy with BAN2401 in Alzheimer’s disease. Alzheimers Res. Ther., 2014, 6(2), 16.
[http://dx.doi.org/10.1186/alzrt246] [PMID: 25031633]
[http://dx.doi.org/10.1186/alzrt246] [PMID: 25031633]
[22]
McDade, E.; Cummings, J.L.; Dhadda, S.; Swanson, C.J.; Reyderman, L.; Kanekiyo, M.; Koyama, A.; Irizarry, M.; Kramer, L.D.; Bateman, R.J. Lecanemab in patients with early Alzheimer’s disease: Detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study. Alzheimers Res. Ther., 2022, 14(1), 191.
[http://dx.doi.org/10.1186/s13195-022-01124-2] [PMID: 36544184]
[http://dx.doi.org/10.1186/s13195-022-01124-2] [PMID: 36544184]
[23]
Van Dyck, C.H.; Swanson, C.J.; Aisen, P.; Bateman, R.J.; Chen, C.; Gee, M.; Kanekiyo, M.; Li, D.; Reyderman, L.; Cohen, S.; Froelich, L.; Katayama, S.; Sabbagh, M.; Vellas, B.; Watson, D.; Dhadda, S.; Irizarry, M.; Kramer, L.D.; Iwatsubo, T. Lecanemab in early Alzheimer’s Disease. N. Engl. J. Med., 2023, 388(1), 9-21.
[http://dx.doi.org/10.1056/NEJMoa2212948] [PMID: 36449413]
[http://dx.doi.org/10.1056/NEJMoa2212948] [PMID: 36449413]
[24]
Sims, J.R.; Zimmer, J.A.; Evans, C.D.; Lu, M.; Ardayfio, P.; Sparks, J.; Wessels, A.M.; Shcherbinin, S.; Wang, H.; Nery, M.E.S.; Collins, E.C.; Solomon, P.; Salloway, S.; Apostolova, L.G.; Hansson, O.; Ritchie, C.; Brooks, D.A.; Mintun, M.; Skovronsky, D.M.; Abreu, R.; Agarwal, P.; Aggarwal, P.; Agronin, M.; Allen, A.; Altamirano, D.; Alva, G.; Andersen, J.; Anderson, A.; Anderson, D.; Arnold, J.; Asada, T.; Aso, Y.; Atit, V.; Ayala, R.; Badruddoja, M.; Jagiello, B.H.; Bajacek, M.; Barton, D.; Bear, D.; Benjamin, S.; Bergeron, R.; Bhatia, P.; Black, S.; Block, A.; Bolouri, M.; Bond, W.; Bouthillier, J.; Brangman, S.; Brew, B.; Brisbin, S.; Brisken, T.; Brodtmann, A.; Brody, M.; Brosch, J.; Brown, C.; Brownstone, P.; Bukowczan, S.; Burns, J.; Cabrera, A.; Capote, H.; Carrasco, A.; Yepez, C.J.; Chavez, E.; Chertkow, H.; Paszkiewicz, C.U.; Ciabarra, A.; Clemmons, E.; Cohen, D.; Cohen, R.; Cohen, I.; Concha, M.; Costell, B.; Crimmins, D.; Cruz-pagan, Y.; Cueli, A.; Cupelo, R.; Czarnecki, M.; Darby, D.; Dautzenberg, P.; De Deyn, P.; De La Gandara, J.; Deck, K.; Dibenedetto, D.; Dibuono, M.; Dinnerstein, E.; Dirican, A.; Dixit, S.; Dobryniewski, J.; Drake, R.; Drysdale, P.; Duara, R.; Duffy, J.; Ellenbogen, A.; Faradji, V.; Feinberg, M.; Feldman, R.; Fishman, S.; Flitman, S.; Forchetti, C.; Fraga, I.; Frank, A.; Frishberg, B.; Fujigasaki, H.; Fukase, H.; Fumero, I.; Furihata, K.; Galloway, C.; Gandhi, R.; George, K.; Germain, M.; Gitelman, D.; Goetsch, N.; Goldfarb, D.; Goldstein, M.; Goldstick, L.; Rojas, G.Y.; Goodman, I.; Greeley, D.; Griffin, C.; Grigsby, E.; Grosz, D.; Hafner, K.; Hart, D.; Henein, S.; Herskowitz, B.; Higashi, S.; Higashi, Y.; Ho, G.; Hodgson, J.; Hohenberg, M.; Hollenbeck, L.; Holub, R.; Hori, T.; Hort, J.; Ilkowski, J.; Ingram, K.J.; Isaac, M.; Ishikawa, M.; Janu, L.; Johnston, M.; Julio, W.; Justiz, W.; Kaga, T.; Kakigi, T.; Kalafer, M.; Kamijo, M.; Kaplan, J.; Karathanos, M.; Katayama, S.; Kaul, S.; Keegan, A.; Kerwin, D.; Khan, U.; Khan, A.; Kimura, N.; Kirk, G.; Klodowska, G.; Kowa, H.; Kutz, C.; Kwentus, J.; Lai, R.; Lall, A.; Lawrence, M.; Lee, E.; Leon, R.; Linker, G.; Lisewski, P.; Liss, J.; Liu, C.; Losk, S.; Lukaszyk, E.; Lynch, J.; Macfarlane, S.; Macsweeney, J.; Mannering, N.; Markovic, O.; Marks, D.; Masdeu, J.; Matsui, Y.; Matsuishi, K.; Mcallister, P.; Mcconnehey, B.; Mcelveen, A.; Mcgill, L.; Mecca, A.; Mega, M.; Mensah, J.; Mickielewicz, A.; Minaeian, A.; Mocherla, B.; Murphy, C.; Murphy, P.; Nagashima, H.; Nair, A.; Nair, M.; Nardandrea, J.; Nash, M.; Nasreddine, Z.; Nishida, Y.; Norton, J.; Nunez, L.; Ochiai, J.; Ohkubo, T.; Okamura, Y.; Okorie, E.; Olivera, E.; O’mahony, J.; Omidvar, O.; Ortiz-Cruz, D.; Osowa, A.; Papka, M.; Parker, A.; Patel, P.; Patel, A.; Patel, M.; Patry, C.; Peckham, E.; Pfeffer, M.; Pietras, A.; Plopper, M.; Porsteinsson, A.; Poulin Robitaille, R.; Prins, N.; Puente, O.; Ratajczak, M.; Rhee, M.; Ritter, A.; Rodriguez, R.; Ables, R.L.; Rojas, J.; Ross, J.; Royer, P.; Rubin, J.; Russell, D.; Rutgers, S.M.; Rutrick, S.; Sadowski, M.; Safirstein, B.; Sagisaka, T.; Scharre, D.; Schneider, L.; Schreiber, C.; Schrift, M.; Schulz, P.; Schwartz, H.; Schwartzbard, J.; Scott, J.; Selem, L.; Sethi, P.; Sha, S.; Sharlin, K.; Sharma, S.; Shiovitz, T.; Shiwach, R.; Sladek, M.; Sloan, B.; Smith, A.; Solomon, P.; Sorial, E.; Sosa, E.; Stedman, M.; Steen, S.; Stein, L.; Stolyar, A.; Stoukides, J.; Sudoh, S.; Sutton, J.; Syed, J.; Szigeti, K.; Tachibana, H.; Takahashi, Y.; Tateno, A.; Taylor, J.D.; Taylor, K.; Tcheremissine, O.; Thebaud, A.; Thein, S.; Thurman, L.; Toenjes, S.; Toji, H.; Toma, M.; Tran, D.; Trueba, P.; Tsujimoto, M.; Turner, R.; Uchiyama, A.; Ussorowska, D.; Vaishnavi, S.; Valor, E.; Vandersluis, J.; Vasquez, A.; Velez, J.; Verghese, C.; Vodickova-borzova, K.; Watson, D.; Weidman, D.; Weisman, D.; White, A.; Willingham, K.; Winkel, I.; Winner, P.; Winston, J.; Wolff, A.; Yagi, H.; Yamamoto, H.; Yathiraj, S.; Yoshiyama, Y.; Zboch, M. Donanemab in early symptomatic alzheimer disease. JAMA, 2023, 330(6), 512-527.
[http://dx.doi.org/10.1001/jama.2023.13239] [PMID: 37459141]
[http://dx.doi.org/10.1001/jama.2023.13239] [PMID: 37459141]
[25]
Rashad, A.; Rasool, A.; Shaheryar, M.; Sarfraz, A.; Sarfraz, Z.; Velasco, R.K.; Ojeda, C.I. Donanemab for Alzheimer’s disease: A systematic review of clinical trials. Healthcare, 2022, 11(1), 32.
[http://dx.doi.org/10.3390/healthcare11010032] [PMID: 36611492]
[http://dx.doi.org/10.3390/healthcare11010032] [PMID: 36611492]
[26]
Ma, Y.S.; Xin, R.; Yang, X.L.; Shi, Y.; Zhang, D.D.; Wang, H.M.; Wang, P.Y.; Liu, J.B.; Chu, K.J.; Fu, D. Paving the way for small-molecule drug discovery. Am. J. Transl. Res., 2021, 13(3), 853-870.
[PMID: 33841626]
[PMID: 33841626]
[27]
Imming, P.; Sinning, C.; Meyer, A. Drugs, their targets and the nature and number of drug targets. Nat. Rev. Drug Discov., 2006, 5(10), 821-834.
[http://dx.doi.org/10.1038/nrd2132] [PMID: 17016423]
[http://dx.doi.org/10.1038/nrd2132] [PMID: 17016423]
[28]
Lipinski, C.A. Lead- and drug-like compounds: The rule-of-five revolution. Drug Discov. Today. Technol., 2004, 1(4), 337-341.
[http://dx.doi.org/10.1016/j.ddtec.2004.11.007] [PMID: 24981612]
[http://dx.doi.org/10.1016/j.ddtec.2004.11.007] [PMID: 24981612]
[29]
Arkin, M.R.; Wells, J.A. Small-molecule inhibitors of protein–protein interactions: Progressing towards the dream. Nat. Rev. Drug Discov., 2004, 3(4), 301-317.
[http://dx.doi.org/10.1038/nrd1343] [PMID: 15060526]
[http://dx.doi.org/10.1038/nrd1343] [PMID: 15060526]
[30]
Li, Q.; Kang, C. Mechanisms of action for small molecules revealed by structural biology in drug discovery. Int. J. Mol. Sci., 2020, 21(15), 5262.
[http://dx.doi.org/10.3390/ijms21155262] [PMID: 32722222]
[http://dx.doi.org/10.3390/ijms21155262] [PMID: 32722222]
[31]
Leeson, P.D.; Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nat. Rev. Drug Discov., 2007, 6(11), 881-890.
[http://dx.doi.org/10.1038/nrd2445] [PMID: 17971784]
[http://dx.doi.org/10.1038/nrd2445] [PMID: 17971784]
[32]
Grossberg, G.T. Cholinesterase inhibitors for the treatment of Alzheimer’s disease: Getting on and staying on. Curr. Ther. Res. Clin. Exp., 2003, 64(4), 216-235.
[http://dx.doi.org/10.1016/S0011-393X(03)00059-6] [PMID: 24944370]
[http://dx.doi.org/10.1016/S0011-393X(03)00059-6] [PMID: 24944370]
[33]
Anand, P.; Singh, B. A review on cholinesterase inhibitors for Alzheimer’s disease. Arch. Pharm. Res., 2013, 36(4), 375-399.
[http://dx.doi.org/10.1007/s12272-013-0036-3] [PMID: 23435942]
[http://dx.doi.org/10.1007/s12272-013-0036-3] [PMID: 23435942]
[34]
Zhao, L.; Ren, T.; Wang, D.D. Clinical pharmacology considerations in biologics development. Acta Pharmacol. Sin., 2012, 33(11), 1339-1347.
[http://dx.doi.org/10.1038/aps.2012.51] [PMID: 23001474]
[http://dx.doi.org/10.1038/aps.2012.51] [PMID: 23001474]
[35]
Gupta, M.; Lee, H.J.; Barden, C.J.; Weaver, D.F. The blood–brain barrier (BBB) score. J. Med. Chem., 2019, 62(21), 9824-9836.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01220] [PMID: 31603678]
[http://dx.doi.org/10.1021/acs.jmedchem.9b01220] [PMID: 31603678]
[36]
Garcês, S.; Demengeot, J. The immunogenicity of biologic therapies. Curr. Probl. Dermatol., 2018, 53, 37-48.
[http://dx.doi.org/10.1159/000478077] [PMID: 29131036]
[http://dx.doi.org/10.1159/000478077] [PMID: 29131036]
[37]
Puranik, G.Y.; Thorn, C.F.; Lamba, J.K.; Leeder, J.S.; Song, W.; Birnbaum, A.K.; Altman, R.B.; Klein, T.E. Valproic acid pathway. Pharmacogenet. Genomics, 2013, 23(4), 236-241.
[http://dx.doi.org/10.1097/FPC.0b013e32835ea0b2] [PMID: 23407051]
[http://dx.doi.org/10.1097/FPC.0b013e32835ea0b2] [PMID: 23407051]
[38]
Srivastava, P.; Tripathi, P.N.; Sharma, P.; Rai, S.N.; Singh, S.P.; Srivastava, R.K.; Shankar, S.; Shrivastava, S.K. Design and development of some phenyl benzoxazole derivatives as a potent acetylcholinesterase inhibitor with antioxidant property to enhance learning and memory. Eur. J. Med. Chem., 2019, 163, 116-135.
[http://dx.doi.org/10.1016/j.ejmech.2018.11.049] [PMID: 30503937]
[http://dx.doi.org/10.1016/j.ejmech.2018.11.049] [PMID: 30503937]
[39]
Weaver, D.F. Trickle-down therapeutics: Entitlement and deprivation in the treatment of Alzheimer’s disease. Can. J. Neurol. Sci., 2022, 49(6), 764-766.
[http://dx.doi.org/10.1017/cjn.2021.207] [PMID: 34486959]
[http://dx.doi.org/10.1017/cjn.2021.207] [PMID: 34486959]
[40]
Golzari-Sorkheh, M.; Brown, C.E.; Weaver, D.F.; Reed, M.A. The NLRP3 inflammasome in the pathogenesis and treatment of Alzheimer’s Disease. J. Alzheimers Dis., 2021, 84(2), 579-598.
[http://dx.doi.org/10.3233/JAD-210660] [PMID: 34569958]
[http://dx.doi.org/10.3233/JAD-210660] [PMID: 34569958]
[41]
Weaver, D.F. Druggable targets for the immunopathy of Alzheimer’s disease. RSC Med. Chem., 1661, 14(9)(1645), 1661.
[http://dx.doi.org/10.1039/D3MD00096F] [PMID: 37731705]
[http://dx.doi.org/10.1039/D3MD00096F] [PMID: 37731705]