Author(s):
Bhakti Y. Sabale, Nidhi N. Shimpi, Akash V. Rahinj, Vaibhav V. Bangar
Email(s):
bhaktisabale123@gmail.com
DOI:
10.52711/0974-4150.2025.00029 
Address:
Bhakti Y. Sabale1, Nidhi N. Shimpi2, Akash V. Rahinj³, Vaibhav V. Bangar⁴
¹Student, JBVP’S Vidya Niketan College of Pharmacy, Lakhewadi.
²Student, JBVP’S Vidya Niketan College of Pharmacy, Lakhewadi.
³Student, JBVP’S Vidya Niketan College of Pharmacy, Lakhewadi.
⁴Student, Kishori College of Pharmacy, Beed.
*Corresponding Author
Published In:
Volume - 18,
Issue - 3,
Year - 2025
ABSTRACT:
ABSTRACT:
Biopharmaceuticals, or protein-based drugs, have been established as safe and effective treatments for various diseases. The first generation of these therapies primarily mimicked native human proteins or blocked their functions using monoclonal antibodies. However, recent innovations in biopharmaceutical design have expanded beyond these limitations. These advancements include computational techniques for altering protein structures, enhanced screening methods for synthesizing and testing new protein libraries, and novel approaches to modifying proteins both post-translationally and during production. Now, protein drug structure and function can be fine-tuned similarly to how small molecules are optimized through medicinal chemistry. This review explores the latest developments in the field of protein 'medicinal biology' and illustrates how these tools are being used to create the next generation of biopharmaceuticals with improved drug properties and novel functionalities.
Cite this article:
Bhakti Y. Sabale, Nidhi N. Shimpi, Akash V. Rahinj, Vaibhav V. Bangar. Advancing Protein Therapeutics: Innovations In Rational Drug Design: A Review. Asian Journal of Research in Chemistry.2025; 18(3):179-4. doi: 10.52711/0974-4150.2025.00029
Cite(Electronic):
Bhakti Y. Sabale, Nidhi N. Shimpi, Akash V. Rahinj, Vaibhav V. Bangar. Advancing Protein Therapeutics: Innovations In Rational Drug Design: A Review. Asian Journal of Research in Chemistry.2025; 18(3):179-4. doi: 10.52711/0974-4150.2025.00029 Available on: https://ajrconline.org/AbstractView.aspx?PID=2025-18-3-11
REFERENCES:
1. Walsh G. Biopharmaceutical Benchmarks. Nat Biotechnol. 2003; 21(8): 865-870.
2. Reichert JM. Trends in development and approval times for new therapeutics in the United States. Nat Rev Drug Discov. 2003; 2(9): 695-702.
3. Pavlou AK, Reichert JM. Recombinant protein therapeutics – success rates, market trends and values to 2010. Nat Biotechnol. 2004; 22(12): 1513-1519.
4. Bonin-Debs AL, Boche I, Gille H, Brinkmann U. Development of secreted proteins as biotherapeutic agents. Expert Opin Biol Ther; 2004: 4(4): 551-558.
5. Zambrowicz BP, Sands AT. Knockouts model the 100 best-selling drugs – will they model the next 100? Nat Rev Drug Discov. 2003; 2(1): 38-51.
6. White CA, Larocca A, Grillo-Lopez AJ. Anti-CD20 monoclonal antibodies as novel treatments for non-Hodgkin’s lymphoma. Pharm Sci Technol Today. 1999; 2(3): 95-101.
7. Grillo-Lopez AJ: Zevalin. The first radioimmunotherapy approved for the treatment of lymphoma. Expert Rev Anticancer Therapy. 2002; 2(5): 485-493.
8. Friedberg JW, Fisher RI. Iodine-131 tositumomab (Bexxar): Radioimmunoconjugate therapy for indolent and transformed B-cell non-Hodgkin’s lymphoma. Expert Rev Anticancer Therapy. 2004; 4(1): 18-26.
9. Marshall SA, Lazar GA, Chirino AJ, Desjarlais JR. Rational design and engineering of therapeutic proteins. Drug Disc Today. 2003; 8(5): 212-221.
10. Vasserot AP, Dickinson CD, Tang Y, Huse WD, Manchester KS, Watkins JD. Optimization of protein therapeutics by directed evolution. Drug Disc Today. 2003; 8(3): 118-126.
11. Leong SR, Chang JC, Ong R, Dawes G, Stemmer WP, Punnonen J. Optimized expression and specific activity of IL-12 by directed molecular evolution. Proc Natl Acad Sci USA. 2003; 100(3): 1163-1168.
12. Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, Teoh LA, Fischkoff SA, Chartash EK. Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: The ARMADA trial. Arthritis Rheum. 2003; 48(1): 35-45.
13. Hayes RJ, Bentzien J, Ary ML, Hwang MY, Jacinto JM, Vielmetter J, Kundu A, Dahiyat BI. Combining computational and experimental screening for rapid optimization of protein properties. Proc Natl Acad Sci USA. 2002; 99(25): 15926-15931.
14. Baigent G: Recombinant interleukin-2 (rIL-2), aldesleukin. J Biotechnol. 2002; 95(3): 277-280.
15. Horowski R. Multiple sclerosis and interferon β-1b, past, present and future. Clin Neurol Neurosurg. 2002; 104(3): 259-264.
16. Sarkar CA, Lowenhaupt K, Horan T, Boone TC, Tidor B, Lauffenburger DA. Rational cytokine design for increased lifetime and enhanced potency using pH-activated “histidine switching”. Nat Biotechnol. 2002; 20(9): 908-913.
17. Hinton PR, Johlfs MG, Xiong JM, Hanestad K, Ong KC, Bullock C, Keller S, Tang MT, Tso JY, Vasquez M, Tsurushita N. Engineered human IgG antibodies with longer serum half-lives in primates. J Biol Chem. 2004; 279(8): 6213-6216.
18. Filikov AV, Hayes RJ, Luo P, Stark DM, Chan C, Kundu A, Dahiyat BI. Computational stabilization of human growth hormone. Protein Sci. 2002; 11(6): 1452-1461.
19. Luo P, Hayes RJ, Chan C, Stark DM, Hwang MY, Jacinto JM, Juvvadi P, Chung HS, Kundu A, Ary ML, Dahiyat BI. Development of a cytokine analog with enhanced stability using computational ultrahigh throughput screening. Protein Sci. 2002; 11(5): 1218-1226.
20. Chance RE, Frank BH, Radziuk JM, DiMarchi RD. Discovery and development of insulin lispro. Drugs Today. 1998; 34(Suppl C): 1-9.
21. Reynolds NA, Wagstaff AJ. Insulin aspart: A review of its use in the management of type 1 or 2 diabetes mellitus. Drugs. 2004; 64(17): 1957-1974.
22. Gerich JE. Insulin glargine: Long-acting basal insulin analog for improved metabolic control. Curr Med Res Opin. 2004; 20(1): 31-37.
23. Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, Watier H. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcγRIIIa gene. Blood. 2002; 99(3): 754-758.
24. Shields RL, Namenuk AK, Hong K, Meng YG, Rae J, Briggs J, Xie D, Lai J, Stadlen A, Li B, Fox JA et al. High resolution mapping of the binding site on human IgG1 for FcγRI, FcγRII, FcγRIII and FcRn and design of IgG1 variants with improved binding to the FcγR. J Biol Chem. 2001; 276(9): 6591-6604.
25. Griffiths AD, Duncan AR. Strategies for selection of antibodies by phage display. Curr Opin Biotechnol. 1998; 9(1):102-108.
26. Kellermann SA, Green LL. Antibody discovery: The use of transgenic mice to generate human monoclonal antibodies for therapeutics. Curr Opin Biotechnol. 2002; 13(6): 593-597.
27. Murray KM, Dahl SL: Recombinant human tumor necrosis factor receptor (p75) Fc fusion protein (TNFR:Fc) in rheumatoid arthritis. Ann Pharmacother. 1997; 31(11): 1335-1338.
28. Dall’Era M, Davis J. CTLA4Ig. A novel inhibitor of costimulation. Lupus. 2004; 13(5): 372-376.
29. Zocher M, Baeuerle PA. A bispecific single-chain antibody fusion protein for targeted depletion of autoreactive B cells via unstimulated human T lymphocytes. Mol Immunol. 2004; 41(5): 511-518.
30. Bitonti AJ, Dumont JA, Low SC, Peters RT, Kropp KE, Palombella VJ, Stattel JM, Lu Y, Tan CA, Song JJ, Garcia AM et al. Pulmonary delivery of an erythropoietin Fc fusion protein in non-human primates through an immunoglobulin transport pathway. Proc NatlAcad Sci USA. 2004; 101(26): 9763-9768.
31. Santoro SW, Wang L, Herberich B, King DS, Schultz PG: An efficient system for the evolution of aminoacyl-tRNA synthetase specificity. Nat Biotechnol. 2002; 20(10): 1044-1048.
32. Zhang Z, Alfonta L, Tian F, Bursulaya B, Uryu S, King DS, Schultz PG. Selective incorporation of 5-hydroxytryptophan into proteins in mammalian cells. Proc Natl Acad Sci USA. 2004; 101(24): 8882-8887.
33. Gerngross TU. Advances in the production of human therapeutic proteins in yeasts and filamentous fungi. Nat Biotechnol. 2004; 22(11): 1409-1414.
34. Sodoyer R. Expression systems for the production of recombinant pharmaceuticals. BioDrugs. 2004; 18(1):51-62.
35. Gomord V, Faye L. Posttranslational modification of therapeutic proteins in plants. Curr Opin Plant Biol. 2004; 7(2):171-181.
36. Elliott S, Lorenzini T, Asher S, Aoki K, Brankow D, Buck L, Busse L, Chang D, Fuller J, Grant J, Hernday N et al. Enhancement of therapeutic protein in vivo activities through glycoengineering. Nat Biotechnol. 2003; 21(4):414-421.
37. Elliott S, Chang D, Delorme E, Eris T, Lorenzini T. Structural requirements for additional N-linked carbohydrate on recombinant human erythropoietin. J Biol Chem. 2004; 279(16): 16854-16862.
38. Umaña P, Jean-Mairet J, Moudry R, Amstutz H, Bailey JE. Engineered glycoforms of an antineuroblastoma IgG1 with optimized antibody-dependent cellular cytotoxic activity. Nat Biotechnol. 1999; 17(2): 176-180.
39. Shinkawa T, Nakamura K, Yamane N, Shoji-Hosaka E, Kanda Y, Sakurada M, Uchida K, Anazawa H, Satoh M, Yamasaki M, Hanai N et al. The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J Biol Chem. 2003; 278(5): 3466-3473.
40. Chirino AJ, Mire-Sluis A. Characterizing biological products and assessing comparability following manufacturing changes. Nat Biotechnol. 2004; 22(11): 1383-1391.
41. Dahiyat B. Antibody Fc engineering. 4th International Congress on Monoclonal Antibodies in Cancer, Colorado Springs, CO, USA 2004.
42. Morpurgo M, Veronese FM. Conjugates of peptides and proteins to polyethylene glycols. Methods Mol Biol. 2004; 283: 45-70.
43. Bailon P, Palleroni A, Schaffer CA, Spence CL, Fung WJ, Porter JE, Ehrlich GK, Pan W, Xu ZX, Modi MW, Farid A et al. Rational design of a potent, long-lasting form of interferon: A 40 kDa branched polyethylene glycol-conjugated interferon α-2a for the treatment of hepatitis C. Bioconjug Chem. 2001; 12(2): 195-202.
44. Steed PM, Tansey MG, Zalevsky J, Zhukovsky EA, Desjarlais JR, Szymkowski DE, Abbott C, Carmichael D, Chan C, Cherry L, Cheung P et al. Inactivation of TNF signaling by rationally designed dominant-negative TNF variants. Science. 2003; 301(5641):1895-1898.
45. Li J, Yang C, Xia Y, Bertino A, Glaspy J, Roberts M, Kuter DJ. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001; 98(12):3241-3248.
46. Sievers EL. Antibody-targeted chemotherapy of acute myeloid leukemia using gemtuzumab ozogamicin (Mylotarg). Blood Cells Mol Dis. 2003; 31(1):7-10.
47. Murphy JR, vanderSpek JC. Targeting diphtheria toxin to growth factor receptors. Semin Cancer Biol. 1995; 6(5): 259-267.
48. Barnett AH. Exubera inhaled insulin: A review. Int J Clin Pract. 2004; 58(4): 394-401.
49. Chirino AJ, Ary ML, Marshall SA. Minimizing the immunogenicity of protein therapeutics. Drug Disc Today. 2004; 9(2): 82-90.
50. Tangri S, LiCalsi C, Sidney J, Sette A. Rationally engineered proteins or antibodies with absent or reduced immunogenicity. Curr Med Chem. 2002; 9(24):2191-2199.
51. XENCOR (Lazar GA, Chirino AJ, Dang W, Desjarlais JR, Doberstein SK, Hayes RJ, Karki SB, Vafa O): Optimized Fc variants and methods for their generation. US-20040132101 (2004).
52. XENCOR (Desjarlais JR, Zhukovsky E, Thomason AR): BAFF variants and methods thereof. WO-2004081043 (2004).