Recent advances, strategies, and future perspectives of peptide-based drugs in clinical applications

Abstract

Peptide-based therapies have attracted considerable interest in the treatment of cancer, diabetes, bacterial infections, and neurodegenerative diseases due to their promising therapeutic properties and enhanced safety profiles. This review provides a comprehensive overview of the major trends in peptide drug discovery and development, emphasizing preclinical strategies aimed at improving peptide stability, specificity, and pharmacokinetic properties. It assesses the current applications and challenges of peptide-based drugs in these diseases, illustrating the pharmaceutical areas where peptide-based drugs demonstrate significant potential. Furthermore, this review analyzes the obstacles that must be overcome in the future, aiming to provide valuable insights and references for the continued advancement of peptide-based drugs.

Keywords

Peptide-based drugs / Oncology / Diabetes / Antimicrobial peptides / Neurodegenerative diseases

References

[1] Lau JL, Dunn MK. Therapeutic peptides: historical perspectives, current development trends, and future directions. Bioorg Med Chem. 2018; 26(10):2700-2707. https://doi.org/10.1016/j.bmc.2017.06.052.

[2] Muttenthaler M, King GF, Adams DJ, et al. Trends in peptide drug discovery. Nat Rev Drug Discov. 2021; 20(4):309-325. https://doi.org/10.1038/s41573-020-00135-8.

[3] Research GV. Peptide therapeutics market size, share & trends analysis report by application, by type of manufacturers, by route of administration, by synthesis technology, by region, and segment forecasts, 2024-2030. Report No. 978-1-68038-179-5. Grand View Research, San Francisco, 2022:110. 2022:110

[4] Novo Nordisk’s blockbuster Ozempic boasts 23% sales surge in 2023. https://www.pharmaceutical-technology.com/analyst-comment/novo-nordisk-ozempic/

[5] Tirzepatide, introduced by Eli Lilly in May 2022, recorded sales of USD 2.958 billion over the same period. https://www.fiercepharma.com/pharma/q1-lilly-takes-over-top-spot-novo-and-could-stay-there-while

[6] Sharma K, Sharma KK, Sharma A, et al. Peptide-based drug discovery: current status and recent advances. Drug Discov Today. 2023; 28(2):103464. https://doi.org/10.1016/j.drudis.2022.103464.

[7] Strohl WR. Fusion proteins for half-life extension of biologics as a strategy to make biobetters. Biodrugs. 2015; 29(4):215-239. https://doi.org/10.1007/s40259-015-0133-6.

[8] Kurtzhals P, Ostergaard S, Nishimura E, et al. Derivatization with fatty acids in peptide and protein drug discovery. Nat Rev Drug Discov. 2023; 22(1):59-80. https://doi.org/10.1038/s41573-022-00529-w.

[9] Lee MF, Poh CL. Strategies to improve the physicochemical properties of peptide-based drugs. Pharm Res. 2023; 40(3):617-632. https://doi.org/10.1007/s11095-023-03486-0.

[10] Liu X, Liu X, Sunchen S, et al. A novel tumor-activated ALA fusion protein for specific inhibition on the growth and invasion of breast cancer cells MDA-MB-231. Drug Deliv. 2017; 24(1):1811-1817. https://doi.org/10.1080/10717544.2017.1406560.

[11] Shen X, Li Q, Wang F, et al. Generation of a novel long-acting thymosin alpha1-Fc fusion protein and its efficacy for the inhibition of breast cancer in vivo. Biomed Pharmacother. 2018; 108:610-617. https://doi.org/10.1016/j.biopha.2018.09.064.

[12] Wang F, Li B, Fu P, et al. Immunomodulatory and enhanced antitumor activity of a modified thymosin alpha1 in melanoma and lung cancer. Int J Pharm. 2018; 547(1-2):611-620. https://doi.org/10.1016/j.ijpharm.2018.06.041.

[13] Shen X, Wang L, Xu C, et al. Fusion of thymosin alpha 1 with mutant IgG1 CH3 prolongs half-life and enhances antitumor effects in vivo. Int Immunopharmacol. 2019;74:105662. https://doi.org/10.1016/j.intimp.2019.05.047.

[14] Li C, Zhao N, An L, et al. Apoptosis-inducing activity of synthetic hydrocarbon-stapled peptides in H358 cancer cells expressing KRAS(G12C). Acta Pharm Sin B. 2021; 11(9):2670-2684. https://doi.org/10.1016/j.apsb.2021.06.013.

[15] Chen J, Bian J, Hantash BM, et al. Enhanced skin retention and permeation of a novel peptide via structural modification, chemical enhancement, and microneedles. Int J Pharm. 2021;606:120868. https://doi.org/10.1016/j.ijpharm.2021.120868.

[16] Yao J, Fan Y, Li Y, et al. Strategies on the nuclear-targeted delivery of genes. J Drug Target. 2013; 21(10):926-939. https://doi.org/10.3109/1061186X.2013.830310.

[17] Xu M, Chen Y, Banerjee P, et al. Dendritic cells targeting and pH-responsive multi-layered nanocomplexes for smart delivery of DNA vaccines. AAPS PharmSciTech. 2017; 18:2618-2625. https://doi.org/10.1208/s12249-017-0741-1.

[18] Wang YT, Huang LP, Shen Y, et al. Electrostatic interactions between polyglutamic acid and polylysine yields stable polyion complex micelles for deoxypodophyllotoxin delivery. Int J Nanomed. 2017; 12:7963-7977. https://doi.org/10.2147/IJN.S140573.

[19] Xu Y, Lu S, Liu Q, et al. Preparation, intestinal segment stability, and mucoadhesion properties of novel thymopentin-loaded chitosan derivatives coated with poly (n-butyl) cyanoacrylate nanoparticles. Int J Nanomedicine. 2019; 14:1659-1668. https://doi.org/10.2147/IJN.S194529.

[20] Merrifield RB. Solid-phase peptide synthesis. Adv Enzymol Relat Areas Mol Biol. 1969; 32:221-296. https://doi.org/10.1002/9780470122778.ch6.

[21] Agouridas V, Diemer V, Melnyk O. Strategies and open questions in solid-phase protein chemical synthesis. Curr Opin Chem Biol. 2020; 58:1-9. https://doi.org/10.1016/j.cbpa.2020.02.007.

[22] Sharma A, Kumar A, De La Torre BG, et al. Liquid-phase peptide synthesis (LPPS): a third wave for the preparation of peptides. Chem Rev. 2022; 122(16):13516-13546. https://doi.org/10.1021/acs.chemrev.2c00132.

[23] Ahn CB, Cho YS, Je JY. Purification and anti-inflammatory action of tripeptide from salmon pectoral fin byproduct protein hydrolysate. Food Chem. 2015; 168:151-156. https://doi.org/10.1016/j.foodchem.2014.05.112.

[24] Chalamaiah M, Hemalatha R, Jyothirmayi T, et al. Immunomodulatory effects of protein hydrolysates rohu (Labeo rohita) egg (roe) in BALB/c mice. Food Res Int. 2014; 62:1054-1061. https://doi.org/10.1016/j.foodres.2014.05.050.

[25] Moreno-Montoro M, Jauregi P, Navarro-Alarcón M, et al. Bioaccessible peptides released by in vitro gastrointestinal digestion of fermented goat milks. Anal Bioanal Chem. 2018; 410(15):3597-3606. https://doi.org/10.1007/s00216-018-0983-0.

[26] Piers KL, Brown MH, Hancock REW. Recombinant-DNA procedures for producing small antimicrobial cationic peptides in bacteria. Gene. 1993; 134(1):7-13. https://doi.org/10.1016/0378-1119(93)90168-3.

[27] Herbel V, Schäfer H, Wink M. Recombinant production of snakin-2 (an antimicrobial peptide from tomato) in and analysis of its bioactivity. Molecules. 2015; 20(8):14889-14901. https://doi.org/10.3390/molecules200814889.

[28] Qiao X, Wang Y, Yu H. Progress in the mechanisms of anticancer peptides. Chin J Biotechnol. 2019; 35(8):1391-1400. https://doi.org/10.13345/j.cjb.190033.

[29] Hilchie AL, Hoskin DW, Power Coombs MR. Anticancer activities of natural and synthetic peptides. Adv Exp Med Biol. 2019; 1117:131-147. https://doi.org/10.1007/978-981-13-3588-4_9.

[30] Chiangjong W, Chutipongtanate S, Hongeng S. Anticancer peptide: physicochemical property, functional aspect and trend in clinical application (Review). Int J Oncol. 2020; 57(3):678-696. https://doi.org/10.3892/ijo.2020.5099.

[31] Pan X, Xu J, Jia X. Research progress evaluating the function and mechanism of anti-tumor peptides. Cancer Manag Res. 2020; 12:397-409. https://doi.org/10.2147/CMAR.S232708.

[32] Hu J, Yan M, Pu C, et al. Chemically synthesized matrix metalloproteinase and angiogenesis-inhibiting peptides as anticancer agents. Anticancer Agents Med Chem. 2014; 14(3):483-494. https://doi.org/10.2174/187152061403140207165632.

[33] Wang F, Zhang R, Li B, et al. A cell-internalizing peptide endows tumstatin7 with enhanced antitumor properties. Pharmazie. 2018; 73(12):715-720. https://doi.org/10.1691/ph.2018.8623.

[34] Li HM, Dong ZP, Wang QY, et al. De novo computational design for development of a peptide ligand oriented to VEGFR-3 with high affinity and long circulation. Mol Pharm. 2017; 14(7):2236-2244. https://doi.org/10.1021/acs.molpharmaceut.7b00070.

[35] Setrerrahmane S, Yu J, Hao J, et al. Novel production method of innovative antiangiogenic and antitumor small peptides in Escherichia coli. Drug Des Devel Ther. 2017; 11:3207-3220. https://doi.org/10.2147/DDDT.S136957.

[36] Li M, Xu H, Wang J. Optimized functional and structural design of dual-target LMRAP, a bifunctional fusion protein with a 25-amino-acid antitumor peptide and GnRH Fc fragment. Acta Pharm Sin B. 2020; 10(2):262-275. https://doi.org/10.1016/j.apsb.2019.10.010.

[37] Kirkwood JM, Butterfield LH, Tarhini AA, et al. Immunotherapy of cancer in 2012. CA Cancer J Clin. 2012; 62(5):309-335. https://doi.org/10.3322/caac.20132.

[38] Kennedy LB, Salama AKS. A review of cancer immunotherapy toxicity. CA Cancer J Clin. 2020; 70(2):86-104. https://doi.org/10.3322/caac.21596.

[39] Carlisle JW, Steuer CE, Owonikoko TK, et al. An update on the immune landscape in lung and head and neck cancers. CA Cancer J Clin. 2020; 70(6):505-517. https://doi.org/10.3322/caac.21630.

[40] Miao Q, Zhang W, Zhang K, et al. Rational design of a potent macrocyclic peptide inhibitor targeting the PD-1/PD-L1 protein-protein interaction. RSC Adv. 2021; 11(38):23270-23279. https://doi.org/10.1039/D1RA03118J.

[41] Tao H, Cheng L, Liu L, et al. A PD-1 peptide antagonist exhibits potent anti-tumor and immune regulatory activity. Cancer Lett. 2020; 493:91-101. https://doi.org/10.1016/j.canlet.2020.08.009.

[42] Tsiatas M, Mountzios G, Curigliano G. Future perspectives in cancer immunotherapy. Ann Transl Med. 2016; 4(14):273. https://doi.org/10.21037/atm.2016.07.14.

[43] Wei X, Chen F, Xin K, et al. Cancer-testis antigen peptide vaccine for cancer immunotherapy: progress and prospects. Transl Oncol. 2019; 12(5):733-738. https://doi.org/10.1016/j.tranon.2019.02.008.

[44] Wang Q, Dong Z, Lou F, et al. Phenylboronic ester-modified polymeric nanoparticles for promoting TRP2 peptide antigen delivery in cancer immunotherapy. Drug Deliv. 2022; 29(1):2029-2043. https://doi.org/10.1080/10717544.2022.2086941.

[45] Shi W, Qiu Q, Tong Z, et al. Synthetic tumor-specific antigenic peptides with a strong affinity to HLA-A2 elicit anti-breast cancer immune response through activating CD8⁽⁺⁾ T cells. Eur J Med Chem. 2020;189:112051. https://doi.org/10.1016/j.ejmech.2020.112051.

[46] Wang M, Liu J, Xia M, et al. Peptide-drug conjugates: a new paradigm for targeted cancer therapy. Eur J Med Chem. 2024;265:116119. https://doi.org/10.1016/j.ejmech.2023.116119.

[47] Youn Y S, Bae YH. Perspectives on the past, present, and future of cancer nanomedicine. Adv Drug Deliv Rev. 2018; 130:3-11. https://doi.org/10.1016/j.addr.2018.05.008.

[48] Hossen S, Hossain MK, Basher MK, et al. SmSmart nanocarrier-based drug delivery systems for cancer therapy and toxicity studies: a review. J Adv Res. 2019; 15:1-18. https://doi.org/10.1016/j.jare.2018.06.005.

[49] Li T, Lu XM, Zhang MR, et al. Peptide-based nanomaterials: self-assembly, properties and applications. Bioact Mater. 2021; 11:268-282. https://doi.org/10.1016/j.bioactmat.2021.09.029.

[50] Wang Y, Cheetham AG, Angacian G, et al. Peptide-drug conjugates as effective prodrug strategies for targeted delivery. Adv Drug Deliv Rev. 2017;110-111:112-126. https://doi.org/10.1016/j.addr.2016.06.015.

[51] Li S, Roberts RW. A novel strategy for in vitro selection of peptide-drug conjugates. Chem Biol. 2003; 10(3):233-239. https://doi.org/10.1016/S1074-5521(03)00047-4.

[52] Cooper BM, Iegre J, Dh OD, et al. Peptides as a platform for targeted therapeutics for cancer: peptide-drug conjugates (PDCs). Chem Soc Rev. 2021; 50(3):1480-1494. https://doi.org/10.1039/D0CS00556H.

[53] Hoppenz P, Els-Heindl S, Beck-Sickinger AG. Peptide-drug conjugates and their targets in advanced cancer therapies. Front Chem. 2020;8:571. https://doi.org/10.3389/fchem.2020.00571.

[54] Chen Z, Zhang P, Cheetham AG, et al. Controlled release of free doxorubicin from peptide-drug conjugates by drug loading. J Control Release. 2014; 191:123-130. https://doi.org/10.1016/j.jconrel.2014.05.051.

[55] Zhou J, Zou Y, Cai Y, et al. A designed cyclic peptide based on trastuzumab used to construct peptide-drug conjugates for its HER2-targeting ability. Bioorg Chem. 2021;117:105453. https://doi.org/10.1016/j.bioorg.2021.105453.

[56] Liu D, Chen Y, Wang Q, et al. Tailored protein-conjugated DNA nanoplatform for synergistic cancer therapy. J Control Release. 2022; 346:250-259. https://doi.org/10.1016/j.jconrel.2022.04.022.

[57] Meng FF, Han N, Yeo Y. Organic nanoparticle systems for spatiotemporal control of multimodal chemotherapy. Expert Opin Drug Del. 2017; 14(3):427-446. https://doi.org/10.1080/17425247.2016.1218464.

[58] He Y, Su Z, Xue L, et al. Co-delivery of erlotinib and doxorubicin by pH-sensitive charge conversion nanocarrier for synergistic therapy. J Control Release. 2016; 229:80-92. https://doi.org/10.1016/j.jconrel.2016.03.001.

[59] Hu D, Mezghrani O, Zhang L, et al. GE11 peptide modified and reduction-responsive hyaluronic acid-based nanoparticles induced higher efficacy of doxorubicin for breast carcinoma therapy. Int J Nanomedicine. 2016; 11:5125-5147. https://doi.org/10.2147/IJN.S113469.

[60] Peng J, Wang Q, Zhou J, et al. Targeted lipid nanoparticles encapsulating dihydroartemisinin and chloroquine phosphate for suppressing the proliferation and liver metastasis of colorectal cancer. Front Pharmacol. 2021;12:720777. https://doi.org/10.3389/fphar.2021.720777.

[61] Yao Y, Chen H, Tan N. Cancer-cell-biomimetic nanoparticles systemically eliminate hypoxia tumors by synergistic chemotherapy and checkpoint blockade immunotherapy. Acta Pharm Sin B. 2022; 12(4):2103-2119. https://doi.org/10.1016/j.apsb.2021.10.010.

[62] Zhang W, Han B, Gao C, et al. Integrated platform of oxygen self-enriched nanovesicles: SP94 peptide-directed chemo/sonodynamic therapy for liver cancer. Eur J Pharm Biopharm. 2022; 179:206-220. https://doi.org/10.1016/j.ejpb.2022.09.012.

[63] Li F, Zhao Y, Mao C, et al. RGD-modified albumin nanoconjugates for targeted delivery of a porphyrin photosensitizer. Mol Pharm. 2017; 14(8):2793-2804. https://doi.org/10.1021/acs.molpharmaceut.7b00321.

[64] Deng Y, Jiang Z, Jin Y, et al. Reinforcing vascular normalization therapy with a bi-directional nano-system to achieve therapeutic-friendly tumor microenvironment. J Control Release. 2021; 340:87-101. https://doi.org/10.1016/j.jconrel.2021.10.016.

[65] Liu Y, Lu X, Zhang Z, et al. mPEG-Cholic acid/TPGS mixed micelles for combined delivery of paclitaxel and bufalin to treat hepatocellular carcinoma. Pharm Dev Technol. 2022; 27(2):215-227. https://doi.org/10.1080/10837450.2022.2037140.

[66] Chen Q, Zhou S, Ding Y, et al. A bio-responsive, cargo-catchable gel for postsurgical tumor treatment via ICD-based immunotherapy. J Control Release. 2022; 346:212-225. https://doi.org/10.1016/j.jconrel.2022.04.015.

[67] Gu Y, Xu C, Wang Y, et al. Multifunctional nanocomposites based on liposomes and layered double hydroxides conjugated with glycylsarcosine for efficient topical drug delivery to the posterior segment of the eye. Mol Pharm. 2019; 16(7):2845-2857. https://doi.org/10.1021/acs.molpharmaceut.8b01136.

[68] Qin C, He B, Dai W, et al. Inhibition of metastatic tumor growth and metastasis via targeting metastatic breast cancer by chlorotoxin-modified liposomes. Mol Pharm. 2014; 11(10):3233-3241. https://doi.org/10.1021/mp400691z.

[69] Wu J, Zhao J, Zhang B, et al. Polyethylene glycol-polylactic acid nanoparticles modified with cysteine-arginine-glutamic acid-lysine-alanine fibrin-homing peptide for glioblastoma therapy by enhanced retention effect. Int J Nanomedicine. 2014; 9:5261-5271. https://doi.org/10.2147/IJN.S72649.

[70] Mohammapdour R, Ghandehari H. Mechanisms of immune response to inorganic nanoparticles and their degradation products. Adv Drug Deliv Rev. 2022;180:114022. https://doi.org/10.1016/j.addr.2021.114022.

[71] Chambre L, Martin-Moldes Z, Parker RN, et al. Bioengineered elastin- and silk-biomaterials for drug and gene delivery. Adv Drug Deliv Rev. 2020; 160:186-198. https://doi.org/10.1016/j.addr.2020.10.008.

[72] Yu LN, Jin Y, Song MJ, et al. When natural compounds meet nanotechnology: nature-inspired nanomedicines for cancer immunotherapy. Pharmaceutics. 2022; 14(8):1589. https://doi.org/10.3390/pharmaceutics14081589.

[73] Tang L, Li J, Zhao QQ, et al. Advanced and innovative nano-systems for anticancer targeted drug delivery. Pharmaceutics. 2021; 13(8):1151. https://doi.org/10.3390/pharmaceutics13081151.

[74] Xu Y, Yao Y, Wang L, et al. Hyaluronic acid coated liposomes co-delivery of natural cyclic peptide RA-XII and mitochondrial targeted photosensitizer for highly selective precise combined treatment of colon cancer. Int J Nanomedicine. 2021; 16:4929-4942. https://doi.org/10.2147/IJN.S311577.

[75] Qi GB, Gao YJ, Wang L, et al. Self-assembled peptide-based nanomaterials for biomedical imaging and therapy. Adv Mater. 2018; 30(22):e1703444. https://doi.org/10.1002/adma.201703444.

[76] Shu C, Sabi-Mouka EMB, Wang X, et al. Self-assembly hydrogels as multifunctional drug delivery of paclitaxel for synergistic tumour-targeting and biocompatibility in vitro and in vivo. J Pharm Pharmacol. 2017; 69(8):967-977. https://doi.org/10.1111/jphp.12732.

[77] La MS, Di NC, Onesto V, et al. Self-assembling peptides: from design to biomedical applications. Int J Mol Sci. 2021; 22(23):12662. https://doi.org/10.3390/ijms222312662.

[78] Lee S, Trinh THT, Yoo M, et al. Self-assembling peptides and their application in the treatment of diseases. Int J Mol Sci. 2019; 20(23):5850. https://doi.org/10.3390/ijms20235850.

[79] Jin X, Zhou J, Zhang Z, et al. Doxorubicin combined with betulinic acid or lonidamine in RGD ligand-targeted pH-sensitive micellar system for ovarian cancer treatment. Int J Pharm. 2019;571:118751. https://doi.org/10.1016/j.ijpharm.2019.118751.

[80] Dong Y, Chen Y, Zhu D, et al. Self-assembly of amphiphilic phospholipid peptide dendrimer-based nanovectors for effective delivery of siRNA therapeutics in prostate cancer therapy. J Control Release. 2020; 322:416-425. https://doi.org/10.1016/j.jconrel.2020.04.003.

[81] Zhu D, Zhang H, Huang Y, et al. A self-assembling amphiphilic peptide dendrimer-based drug delivery system for cancer therapy. Pharmaceutics. 2021; 13(7):1092. https://doi.org/10.3390/pharmaceutics13071092.

[82] Shu C, Li TF, Li D, et al. Anticancer activity and pharmacokinetics of tanshinone IIA derivative supramolecular hydrogels. J Drug Deliv Sci Tec. 2018; 48:509-515. https://doi.org/10.1016/j.jddst.2018.10.024.

[83] Sun LL, Zheng CL, Webster TJ. Self-assembled peptide nanomaterials for biomedical applications: promises and pitfalls. Int J Nanomed. 2016; 12:73-86. https://doi.org/10.2147/IJN.S117501.

[84] Gupta S, Singh I, Sharma AK, et al. Ultrashort peptide self-assembly: front-runners to transport drug and gene cargos. Front Bioeng Biotechnol. 2020;8:504. https://doi.org/10.3389/fbioe.2020.00504.

[85] Jiang T, Ma Y, Xu X, et al. Enzyme-instructed hybrid nanogel/nanofiber oligopeptide hydrogel for localized protein delivery. Acta Pharm Sin B. 2021; 11(7):2070-2079. https://doi.org/10.1016/j.apsb.2020.11.010.

[86] Sun J, Jiang L, Lin Y, et al. Enhanced anticancer efficacy of paclitaxel through multistage tumor-targeting liposomes modified with RGD and KLA peptides. Int J Nanomedicine. 2017; 12:1517-1537. https://doi.org/10.2147/IJN.S122859.

[87] Wang X, Zhang Q, Lv L, et al. Glioma and microenvironment dual targeted nanocarrier for improved antiglioblastoma efficacy. Drug Deliv. 2017; 24(1):1401-1409. https://doi.org/10.1080/10717544.2017.1378940.

[88] Ni Y, Zhao W, Cheng W, et al. Lipopeptide liposomes-loaded hydrogel for multistage transdermal chemotherapy of melanoma. J Control Release. 2022; 351:245-254. https://doi.org/10.1016/j.jconrel.2022.09.014.

[89] Zhang S, Liu Y, Gan Y, et al. Conjugates of TAT and folate with DOX-loaded chitosan micelles offer effective intracellular delivery ability. Pharm Dev Technol. 2019; 24(2):253-261. https://doi.org/10.1080/10837450.2018.1469147.

[90] Wu C, Wang Z, Wang X, et al. Morphology/interstitial fluid pressure-tunable nanopomegranate designed by alteration of membrane fluidity under tumor enzyme and PEGylation. Mol Pharm. 2021; 18(5):2039-2052. https://doi.org/10.1021/acs.molpharmaceut.1c00036.

[91] Xiao H, Zhang R, Fan X, et al. Super-sensitive bifunctional nanoprobe: self-assembly of peptide-driven nanoparticles demonstrating tumor fluorescence imaging and therapy. Acta Pharm Sin B. 2022; 12(3):1473-1486. https://doi.org/10.1016/j.apsb.2021.07.020.

[92] Kong Y, Sun Q, Zhao Q, et al. Purification and characterization of a novel antiplatelet peptide from Deinagkistrodon acutus Venom. Toxins (Basel). 2018; 10(8):332. https://doi.org/10.3390/toxins10080332.

[93] Xin XF, Zhou Y, Lyu Y, et al. Disease-specific corona mediated co-delivery of MTX and siRNA-TNFα by a polypeptide nanoplatform with antigen-scavenging functions in psoriasis. J Control Release. 2023; 364:326-342. https://doi.org/10.1016/j.jconrel.2023.10.035.

[94] Raza F, Zafar H, Zhu Y, et al. A review on recent advances in stabilizing peptides/proteins upon fabrication in hydrogels from biodegradable polymers. Pharmaceutics. 2018; 10(1):16. https://doi.org/10.3390/pharmaceutics10010016.

[95] Sun C, Shen WC, Tu J, et al. Interaction between cell-penetrating peptides and acid-sensitive anionic oligopeptides as a model for the design of targeted drug carriers. Mol Pharm. 2014; 11(5):1583-1590. https://doi.org/10.1021/mp400747k.

[96] Yang Y, Zhao QF, Peng Z, et al. A GSH/CB dual-controlled self-assembled nanomedicine for high-efficacy doxorubicin-resistant breast cancer therapy. Front Pharmacol. 2022;12:811724. https://doi.org/10.3389/fphar.2021.811724.

[97] Ouahab A, Cheraga N, Onoja V, et al. Novel pH-sensitive charge-reversal cell penetrating peptide conjugated PEG-PLA micelles for docetaxel delivery: in vitro study. Int J Pharm. 2014; 466(1-2):233-245. https://doi.org/10.1016/j.ijpharm.2014.03.009.

[98] Chen X, Zhang Y, Tang C, et al. Co-delivery of paclitaxel and anti-survivin siRNA via redox-sensitive oligopeptide liposomes for the synergistic treatment of breast cancer and metastasis. Int J Pharm. 2017; 529(1-2):102-115. https://doi.org/10.1016/j.ijpharm.2017.06.071.

[99] Tang B, Zaro JL, Shen Y, et al. Acid-sensitive hybrid polymeric micelles containing a reversibly activatable cell-penetrating peptide for tumor-specific cytoplasm targeting. J Control Release. 2018; 279:147-156. https://doi.org/10.1016/j.jconrel.2018.04.016.

[100] Wang C, Wang X, Zhong T, et al. The antitumor activity of tumor-homing peptide-modified thermosensitive liposomes containing doxorubicin on MCF-7/ADR: in vitro and in vivo. Int J Nanomedicine. 2015; 10:2229-2248. https://doi.org/10.2217/nnm.15.48.

[101] Jin Y, Wu Z, Wu C, et al. Size-adaptable and ligand (biotin)-sheddable nanocarriers equipped with avidin scavenging technology for deep tumor penetration and reduced toxicity. J Control Release. 2020; 320:142-158. https://doi.org/10.1016/j.jconrel.2020.01.040.

[102] Liu Y, Ye Z, Yang W, et al. A triple enhanced permeable gold nanoraspberry designed for positive feedback interventional therapy. J Control Release. 2022; 345:120-137. https://doi.org/10.1016/j.jconrel.2022.03.010.

[103] Li TF, Li D, Xu XY, et al. A simple injectable peptide-based hydrogel of tanshinone IIA for antioxidant and anticoagulation. J Drug Deliv Sci Tec. 2020;58:101532. https://doi.org/10.1016/j.jddst.2020.101532.

[104] Zhu J, Gao R, Wang Z, et al. Sustained and targeted delivery of self-assembled doxorubicin nonapeptides using pH-responsive hydrogels for osteosarcoma chemotherapy. Pharmaceutics. 2023; 15(2):668. https://doi.org/10.3390/pharmaceutics15020668.

[105] Liu YF, Ran YC, Ge Y, et al. pH-Sensitive peptide hydrogels as a combination drug delivery system for cancer treatment. Pharmaceutics.. 2022; 14(3):652. https://doi.org/10.3390/pharmaceutics14030652.

[106] Sun H, Saeedi P, Karuranga S, et al. IDF diabetes atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022; 183:109119. https://doi.org/10.1016/j.diabres.2021.109119.

[107] Klein S, Gastaldelli A, Yki-Jarvinen H, et al. Why does obesity cause diabetes? Cell Metab. 2022; 34(1):11-20. https://doi.org/10.1016/j.cmet.2021.12.012.

[108] Rohm TV, Meier DT, Olefsky JM, et al. Inflammation in obesity, diabetes, and related disorders. Immunity. 2022; 55(1):31-55. https://doi.org/10.1016/j.immuni.2021.12.013.

[109] Wang S, Downing G, Olsen KF, et al. Aqueous remote loading of setmelanotide in poly(lactic-co-glycolic acid) microspheres for long-term obesity treatment. J Control Release. 2023; 364:589-600. https://doi.org/10.1016/j.jconrel.2023.09.015.

[110] Riddle MC, Yuen KC, De Bruin TW, et al. Fixed ratio dosing of pramlintide with regular insulin before a standard meal in patients with type 1 diabetes. Diabetes Obes Metab. 2015; 17(9):904-907. https://doi.org/10.1111/dom.12504.

[111] Yabut JM, Drucker DJ. Glucagon-like peptide-1 receptor-based therapeutics for metabolic liver disease. Endocr Rev. 2023; 44(1):14-32. https://doi.org/10.1210/endrev/bnac018.

[112] Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007; 87(4):1409-1439. https://doi.org/10.1152/physrev.00034.2006.

[113] Helmstadter J, Keppeler K, Kuster L, et al. Glucagon-like peptide-1 (GLP-1) receptor agonists and their cardiovascular benefits-the role of the GLP-1 receptor. Br J Pharmacol. 2022; 179(4):659-676. https://doi.org/10.1111/bph.15462.

[114] Nauck M. Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab. 2016; 18(3):203-216. https://doi.org/10.1111/dom.12591.

[115] Rosenkilde MM. Advances in incretin-based therapeutics for obesity. Nat Rev Endocrinol. 2024; 20(2):67-68. https://doi.org/10.1038/s41574-023-00938-w.

[116] Liu CX, Zou YX, Qian H. GLP-1R agonists for the treatment of obesity: a patent review (2015-present). Expert Opin Ther Pat. 2020; 30(10):781-794. https://doi.org/10.1080/13543776.2020.1811851.

[117] Inokuchi T, Fukumoto Y, Lee G, et al. Efficacy and tolerability of oral semaglutide in Japanese patients with type 2 diabetes mellitus: analysis report from diabetes specialist clinics. J Diabetes Investig. 2024; 15(9):1202-1210. https://doi.org/10.1111/jdi.14225.

[118] Peng HS, Wang JH, Chen JY, et al. Challenges and opportunities in delivering oral peptides and proteins. Expert Opin Drug Del. 2023; 20(10):1349-1369. https://doi.org/10.1080/17425247.2023.2237408.

[119] Nogueiras R, Nauck MA, Tschop MH. Gut hormone co-agonists for the treatment of obesity: from bench to bedside. Nat Metab. 2023; 5(6):933-944. https://doi.org/10.1038/s42255-023-00812-z.

[120] Muller TD, Bluher M, Tschop MH, et al. Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov. 2022; 21(3):201-223. https://doi.org/10.1038/s41573-021-00337-8.

[121] Buckley A, Suliman S, Allum M, et al. Real world use of tirzepatide in the treatment of type 2 diabetes in an Arab population. Diabetes Obes Metab. 2024; 26(8):3381-3391. https://doi.org/10.1111/dom.15680.

[122] Ji L, Gao L, Jiang H, et al. Safety and efficacy of a GLP-1 and glucagon receptor dual agonist mazdutide (IBI362) 9 mg and 10 mg in Chinese adults with overweight or obesity: a randomised, placebo-controlled, multiple-ascending-dose phase 1b trial. EClinicalMedicine. 2022;54:101691. https://doi.org/10.1016/j.eclinm.2022.101691.

[123] Kaur M, Misra S. A review of an investigational drug retatrutide, a novel triple agonist agent for the treatment of obesity. Eur J Clin Pharmacol. 2024; 80(5):669-676. https://doi.org/10.1007/s00228-024-03646-0.

[124] Apovian CM, Mcdonnell ME. CagriSema and the link between obesity and type 2 diabetes. Lancet. 2023; 402(10403):671-673. https://doi.org/10.1016/S0140-6736(23)01291-6.

[125] Tang D, Tian H, Wu J, et al. C-terminal site-specific PEGylated exendin-4 analog: a long-acting glucagon like peptide-1 receptor agonist, on glycemic control and beta cell function in diabetic db/db mice. J Pharmacol Sci. 2018; 138(1):23-30. https://doi.org/10.1016/j.jphs.2018.08.009.

[126] Sun L, Huang X, Han J, et al. Site-specific fatty chain-modified exenatide analogs with balanced glucoregulatory activity and prolonged in vivo activity. Biochem Pharmacol. 2016;110-111:80-91. https://doi.org/10.1016/j.bcp.2016.04.016.

[127] Wu Q, Chen S, Zhu H, et al. Biased agonists with less glucagon-like peptide-1 receptor-mediated endocytosis prolong hypoglycaemic effects. Eur J Pharmacol. 2021;907:174203. https://doi.org/10.1016/j.ejphar.2021.174203.

[128] Gao MM, Tong Y, Gao XD, et al. Development of a C-terminal site-specific PEGylated analog of GLP-1 with improved anti-diabetic effects in diabetic mice. Drug Develop Res. 2013; 74(3):186-193. https://doi.org/10.1002/ddr.21059.

[129] Han J, Chen X, Wang Y, et al. Xenopus GLP-1-inspired discovery of novel GLP-1 receptor agonists as long-acting hypoglycemic and insulinotropic agents with significant therapeutic potential. Biochem Pharmacol. 2017; 142:155-167. https://doi.org/10.1016/j.bcp.2017.06.132.

[130] Han J, Fei Y, Zhou F, et al. Xenopus-derived glucagon-like peptide-1 and polyethylene-glycosylated glucagon-like peptide-1 receptor agonists: long-acting hypoglycaemic and insulinotropic activities with potential therapeutic utilities. Br J Pharmacol. 2018; 175(3):544-557. https://doi.org/10.1111/bph.14107.

[131] Han J, Huang X, Sun L, et al. Novel fatty chain-modified glucagon-like peptide-1 conjugates with enhanced stability and prolonged in vivo activity. Biochem Pharmacol. 2013; 86(2):297-308. https://doi.org/10.1016/j.bcp.2013.05.012.

[132] Han J, Sun L, Huang X, et al. Novel coumarin modified GLP-1 derivatives with enhanced plasma stability and prolonged in vivo glucose-lowering ability. Br J Pharmacol. 2014; 171(23):5252-5264. https://doi.org/10.1111/bph.12843.

[133] Han J, Sun LD, Qian H, et al. Biological activity studies of the novel glucagon-like peptide-1 derivative HJ07. Chin J Nat Med. 2014; 12(8):613-618. https://doi.org/10.1016/S1875-5364(14)60093-5.

[134] Zhang B, He D, Fan Y, et al. Oral delivery of exenatide via microspheres prepared by cross-linking of alginate and hyaluronate. PLoS One. 2014; 9(1):e86064. https://doi.org/10.1371/journal.pone.0086064.

[135] Ruan S, Gu Y, Liu B, et al. Long-acting release microspheres containing novel GLP-1 analog as an antidiabetic system. Mol Pharm. 2018; 15(7):2857-2869. https://doi.org/10.1021/acs.molpharmaceut.8b00344.

[136] Lu W, Tian H, Qian P, et al. An orally available hypoglycaemic peptide taken up by caveolae transcytosis displays improved hypoglycaemic effects and body weight control in db/db mice. Br J Pharmacol. 2020; 177(15):3473-3488. https://doi.org/10.1111/bph.15069.

[137] Aroda VR, Blonde L, Pratley RE. A new era for oral peptides: SNAC and the development of oral semaglutide for the treatment of type 2 diabetes. Rev Endocr Metab Disord. 2022; 23(5):979-994. https://doi.org/10.1007/s11154-022-09735-8.

[138] Wang LJ. Designing a dual GLP-1R/GIPR agonist from tirzepatide: comparing residues between tirzepatide, GLP-1, and GIP. Drug Des Dev Ther. 2022; 16:1547-1559. https://doi.org/10.2147/DDDT.S358989.

[139] Davies J. Where have all the antibiotics gone? Can J Infect Dis Med Microbiol. 2006; 17(5):287-290. https://doi.org/10.1155/2006/707296.

[140] Shallcross LJ, Davies DS. Antibiotic overuse: a key driver of antimicrobial resistance. Br J Gen Pract. 2014; 64(629):604-605. https://doi.org/10.3399/bjgp14X682561.

[141] Wang G, Li X, Wang Z. APD3:the antimicrobial peptide database as a tool for research and education. Nucleic Acids Res. 2016; 44(D1):D1087-1093. https://doi.org/10.1093/nar/gkv1278.

[142] Luo Y, Song Y. Mechanism of antimicrobial peptides: antimicrobial, anti-inflammatory and antibiofilm activities. Int J Mol Sci. 2021; 22(21):11401. https://doi.org/10.3390/ijms222111401.

[143] Kang HK, Kim C, Seo CH, et al. The therapeutic applications of antimicrobial peptides (AMPs): a patent review. J Microbiol. 2017; 55(1):1-12. https://doi.org/10.1007/s12275-017-6452-1.

[144] Hancock RE, Nijnik A, Philpott DJ. Modulating immunity as a therapy for bacterial infections. Nat Rev Microbiol. 2012; 10(4):243-254. https://doi.org/10.1038/nrmicro2745.

[145] Epand RM, Walker C, Epand RF, et al. Molecular mechanisms of membrane targeting antibiotics. Biochim Biophys Acta. 2016; 1858(5):980-987. https://doi.org/10.1016/j.bbamem.2015.10.018.

[146] Khamlek S, Lucksiri A, Sunkonkit K, et al. Treatment outcomes and associated factors of intravenous colistin for nosocomial infections in pediatric patients: a retrospective study in a university hospital in Thailand. Pediatr Infect Dis J. 2024;Online ahead of print. https://doi.org/10.1097/INF.0000000000004450.

[147] Gkartziou F, Plota M, Kypraiou C, et al. Daptomycin liposomes exhibit enhanced activity against staphylococci biofilms compared to free drug. Pharmaceutics. 2024; 16(4):459. https://doi.org/10.3390/pharmaceutics16040459.

[148] Wang P, Liu S, He X, et al. Therapeutic drug monitoring of polymyxin B cerebrospinal fluid concentrations in patients with carbapenem-resistant Gram-negative bacteria-induced central nervous system infection. J Antimicrob Chemother. 2024; 79(8):1969-1973. https://doi.org/10.1093/jac/dkae193.

[149] Browne K, Chakraborty S, Chen R X, et al. A new era of antibiotics: the clinical potential of antimicrobial peptides. Int J Mol Sci. 2020; 21(19):7047. https://doi.org/10.3390/ijms21197047.

[150] Lo SC, Xie ZR, Chang KY. Structural and functional enrichment analyses for antimicrobial peptides. Int J Mol Sci. 2020; 21(22):8783. https://doi.org/10.3390/ijms21228783.

[151] Silva ARP, Guimaraes MS, Rabelo J, et al. Recent advances in the design of antimicrobial peptide conjugates. J Mater Chem B. 2022; 10(19):3587-3600. https://doi.org/10.1039/D1TB02757C.

[152] Bechinger B, Gorr SU. Antimicrobial peptides: mechanisms of action and resistance. J Dent Res. 2017; 96(3):254-260. https://doi.org/10.1177/0022034516679973.

[153] Provias J, Jeynes B. The role of the blood-brain barrier in the pathogenesis of senile plaques in Alzheimer’s disease. Int J Alzheimers Dis. 2014;2014:191863. https://doi.org/10.1155/2014/191863.

[154] Gasca-Salas C, Fernandez-Rodriguez B, Pineda-Pardo JA, et al. Blood-brain barrier opening with focused ultrasound in Parkinson’s disease dementia. Nat Commun. 2021; 12(1):779. https://doi.org/10.1038/s41467-021-21022-9.

[155] Nishihara H, Perriot S, Gastfriend BD, et al. Intrinsic blood-brain barrier dysfunction contributes to multiple sclerosis pathogenesis. Brain. 2022; 145(12):4334-4348. https://doi.org/10.1093/brain/awac019.

[156] Falco-Walter J. Epilepsy-definition classification, pathophysiology, and epidemiology. Semin Neurol. 2020; 40(6):617-623. https://doi.org/10.1055/s-0040-1718719.

[157] Armiento V, Spanopoulou A, Kapurniotu A. Peptide-based molecular strategies to interfere with protein misfolding, aggregation, and cell degeneration. Angew Chem Int Ed Engl. 2020; 59(9):3372-3384. https://doi.org/10.1002/anie.201906908.

[158] Liu KM, Lin HH, Pi RB, et al. Research and development of anti-Alzheimer’s disease drugs: an update from the perspective of technology flows. Expert Opin Ther Pat. 2018; 28(4):341-350. https://doi.org/10.1080/13543776.2018.1439475.

[159] Balestrino R, Schapira AHV. Parkinson disease. Eur J Neurol. 2020; 27(1):27-42. https://doi.org/10.1111/ene.14108.

[160] Shen J, Zha Q, Yang QH, et al. Inhibiting von Hippel-Lindau protein-mediated dishevelled ubiquitination protects against experimental parkinsonism. Acta Pharmacol Sin. 2023; 44(5):940-953. https://doi.org/10.1038/s41401-022-01014-1.

[161] Yao SY, Wang JF, Xu Z, et al. A peptide rich in glycine-serine-alanine repeats ameliorates Alzheimer-type neurodegeneration. Br J Pharmacol. 2023; 180(14):1878-1896. https://doi.org/10.1111/bph.16048.

[162] Liu MC, Yang SJ, Yang JP, et al. Neuroprotective and memory-enhancing effects of antioxidant peptide from walnut (Juglans regia L.) protein hydrolysates. Nat Prod Commun. 2019; 14(7):1-13. https://doi.org/10.1177/1934578X19865838.

[163] Zhang S, Asghar S, Zhu C, et al. Multifunctional nanorods based on self-assembly of biomimetic apolipoprotein E peptide for the treatment of Alzheimer’s disease. J Control Release. 2021; 335:637-649. https://doi.org/10.1016/j.jconrel.2021.05.044.

[164] Guo Q, Xu S, Yang P, et al. A dual-ligand fusion peptide improves the brain-neuron targeting of nanocarriers in Alzheimer’s disease mice. J Control Release. 2020; 320:347-362. https://doi.org/10.1016/j.jconrel.2020.01.039.

[165] Gentilucci L, De Marco R, Cerisoli L. Chemical modifications designed to improve peptide stability: incorporation of non-natural amino acids, pseudo-peptide bonds, and cyclization. Curr Pharm Des. 2010; 16(28):3185-3203. https://doi.org/10.2174/138161210793292555.

[166] Cheng JJ, Zhou JL, Kong LY, et al. Stabilized cyclic peptides as modulators of protein-protein interactions: promising strategies and biological evaluation. Rsc Med Chem. 2023; 14(12):2496-2508. https://doi.org/10.1039/D3MD00487B.

[167] Nattel S, Carlsson L. Innovative approaches to anti-arrhythmic drug therapy. Nat Rev Drug Discov. 2006; 5(12):1034-1049. https://doi.org/10.1038/nrd2112.

[168] Zhang L, Shan X, Meng X, et al. Novel integrin alphavbeta3-specific ligand for the sensitive diagnosis of glioblastoma. Mol Pharm. 2019; 16(9):3977-3984. https://doi.org/10.1021/acs.molpharmaceut.9b00602.

[169] Sagan S, Karoyan P, Lequin O, et al. N- and Calpha-methylation in biologically active peptides: synthesis, structural and functional aspects. Curr Med Chem. 2004; 11(21):2799-2822. https://doi.org/10.2174/0929867043364108.

[170] Cardillo G, Gentilucci L, Qasem AR, et al. Endomorphin-1 analogues containing beta-proline are mu-opioid receptor agonists and display enhanced enzymatic hydrolysis resistance. J Med Chem. 2002; 45(12):2571-2578. https://doi.org/10.1021/jm011059z.

[171] Toniolo C, Crisma M, Formaggio F, et al. Structures of peptides from alpha-amino acids methylated at the alpha-carbon. Biopolymers. 1993; 33(7):1061-1072. https://doi.org/10.1002/bip.360330708.

[172] Haskell-Luevano C, Toth K, Boteju L, et al. beta-Methylation of the Phe7 and Trp9 melanotropin side chain pharmacophores affects ligand-receptor interactions and prolonged biological activity. J Med Chem. 1997; 40(17):2740-2749. https://doi.org/10.1021/jm970018t.

[173] Ando M, Fujimoto M, Takahashi Y, et al. Targeted delivery of interferon gamma using a recombinant fusion protein of a fibrin clot-binding peptide with interferon gamma for cancer gene therapy. J Pharm Sci. 2017; 106(3):892-897. https://doi.org/10.1016/j.xphs.2016.11.018.

[174] Karimi M, Ghasemi A, Sahandi ZP, et al. Smart micro/nanoparticles in stimulus-responsive drug/gene delivery systems. Chem Soc Rev. 2016; 45(5):1457-1501. https://doi.org/10.1039/C5CS00798D.

[175] Moldaver D, Larche M. Immunotherapy with peptides. Allergy. 2011; 66(6):784-791. https://doi.org/10.1111/j.1398-9995.2011.02610.x.

[176] Guo F, Zhang MY, Gao Y, et al. Modified nanoparticles with cell-penetrating peptide and amphipathic chitosan derivative for enhanced oral colon absorption of insulin: preparation and evaluation. Drug Deliv. 2016; 23(6):2003-2014. https://doi.org/10.3109/10717544.2015.1048489.

[177] Yang MY, Lin YJ, Han MM, et al. Pathological collagen targeting and penetrating liposomes for idiopathic pulmonary fibrosis therapy. J Control Release. 2022; 351:623-637. https://doi.org/10.1016/j.jconrel.2022.09.054.