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Current Alzheimer Research

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Mini-Review Article

Drug Design for Alzheimer’s Disease: Biologics vs. Small Molecules

Author(s): Donald F. Weaver*

Volume 20, Issue 12, 2023

Published on: 08 March, 2024

Page: [821 - 826] Pages: 6

DOI: 10.2174/0115672050301583240307114452

Price: $65

Abstract

There shall probably be no “magic bullet” for Alzheimer’s; rather, we should be pursuing a “magic shotgun blast” that will target multiple complementary therapeutic receptors. Although protein misfolding/oligomerization will probably be one of these targets, this alone is insufficient and will require the co-administration of other therapeutic entities engaging targets, such as immunopathy, gliopathy, mitochondriopathy, synaptotoxicity or others. Although polypharmacy is emerging as the preferred therapeutic route, many questions remain unanswered. Should this be a cocktail of biologics, a concoction of small molecules, or a judicious combination of both? Biologics and small molecule drugs display both strengths and weaknesses. When addressing a disease as complex and globally important as Alzheimer’s, there should be room for the continuing development of both of these therapeutic classes. Each has much to offer, and when used with their advantages and disadvantages in clear focus, an ultimate solution will probably require contributions from both.

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[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]
[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]
[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]
[4]
Doytchinova, I. Drug design—past, present, future. Molecules, 2022, 27(5), 1496.
[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]
[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]
[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]
[8]
Morrow, T.; Felcone, L.H. Defining the difference: What makes biologics unique. Biotechnol. Healthc., 2004, 1(4), 24-29.
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]
[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]

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