The Protein Journal最新文献

{"title":"Halved but Potent: Exploring the Inhibitory Property of Curcumin Derivatives Against Evolving SARS-CoV-2 Strains","authors":"Atala Bihari Jena,&nbsp;Umesh Chandra Dash,&nbsp;Asim K Duttaroy","doi":"10.1007/s10930-025-10309-1","DOIUrl":"10.1007/s10930-025-10309-1","url":null,"abstract":"<div><p>In the prevailing pandemic, the emergence of several variants has created concerns, as none of the vaccines have 100% effectiveness. As a countermeasure to combat the infection of SARS-CoV-2 and its variants and to minimize the morbidity, alternative therapeutics have been prioritized, mainly including phytocompounds. In our recent studies, we have considered polyphenols, such as catechin, curcumin, and 8-Hydroxydihydrosanguinarine (8-HDS), for this purpose and found their tendency to bind to the receptor-binding domain of S-protein, thereby inhibiting viral infiltration into the cell. In the current scenario, with the appearance of multiple viral strains, we have furthered our studies on two highly infectious variants of SARS-CoV-2: D614G and B.1.1.7, commonly identified as the UK variant. Our research incorporates various computational methodologies to decipher the potential role of our previously studied phytocompounds and the curcumin derivative, half-curcumin, inhibiting viral attachment and entry for both D614G and the B.1.1.7 lineage. The physicochemical characterization of the spike (S) protein of the UK variant suggests it is less thermostable, which raises questions about its transmissibility in warmer regions of the globe. All the studied phytocompounds have an immense ability to hinder the S protein interaction towards the human cell receptor ACE2 for both the variants. The half-curcumin has also potential drug suitability, which is confirmed through its characterization of ADME (Physicochemical, Water Solubility, Lipophilicity, Drug-likeness, and Pharmacokinetics) properties, and can be considered as a future therapeutic molecule for anti-COVID-19 drug design.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":793,"journal":{"name":"The Protein Journal","volume":"45 2","pages":"384 - 399"},"PeriodicalIF":1.4,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10930-025-10309-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145764776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression and Purification of p70 (∆NH2-146/∆CT104) S6 K, a 57.3 kDa N- and C-Terminal Truncated p70S6 Kinase-GST Fusion Protein in Bacterial Expression System","authors":"Shafat A. Latoo","doi":"10.1007/s10930-025-10308-2","DOIUrl":"10.1007/s10930-025-10308-2","url":null,"abstract":"<div><p>An essential modulator of cell growth and division is the evolutionarily conserved kinase (S6K1). It is triggered by certain stimulants, including amino acids, insulin, and other growth hormones. The Akt/phosphatidylinositol 3-kinase pathway's downstream effector, the serine/threonine kinase S6K1, is consistently activated in a variety of cancer types. Rho family guanosine triphosphate (GTPase) activation and actin filament cross-linking are two of S6K1's roles. The p70 (∆2-146/∆CT104) S6K is a truncated variant of p70S6 kinase, created by removing 146 amino acids from the N-terminal and 104 amino acids from the C-terminal end of the original protein, resulting in a total of 275 amino acids. The p70 (∆2-146/∆CT104) S6K was effectively expressed in the <i>E. coli</i> BL21 (DE3)pLysS strain after being cloned in <i>E. coli</i> DH5α. A rabbit polyclonal anti-GST antibody had been employed during Western blot analysis throughout the protein's production and purification process. Protein purification was achieved by affinity chromatography using glutathione resin-agarose beads, and chromatography onto a spin concentration column was performed. Rabbit polyclonal anti-(p70S6Kinase and GST) antibodies confirmed the presence of the purified protein.</p><h3>Graphic Abstract</h3><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":793,"journal":{"name":"The Protein Journal","volume":"45 2","pages":"245 - 253"},"PeriodicalIF":1.4,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145703668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advantages and Limitations of AlphaFold in Structural Biology: Insights from Recent Studies","authors":"Mandarina Qing Cheng Li,&nbsp;Sihan Wang,&nbsp;Shi-Ruei Lin,&nbsp;Li Eric Ngok Ting,&nbsp;Zhi-Hong Wan,&nbsp;Guodong Xie,&nbsp;Jane Zhang","doi":"10.1007/s10930-025-10310-8","DOIUrl":"10.1007/s10930-025-10310-8","url":null,"abstract":"<div><p>Over the past three years, AlphaFold—a deep learning–based protein structure prediction system—has transformed structural biology by providing near–experimental accuracy models directly from amino acid sequences. This narrative review synthesizes applications reported in the 2022–2025 literature across human, microbial, and viral systems, drawing on peer-reviewed studies as our data source. Representative examples include modeling of SARS-CoV-2 spike and nucleocapsid proteins in virology, assisting cryo-EM interpretation of bacterial ribosomal and membrane-protein complexes in microbiology, and refining conformational hypotheses for human GPCRs in biomedicine. Across these cases, AlphaFold predictions have complemented experimental workflows by accelerating hypothesis generation, improving model fitting within ambiguous density regions (poorly resolved areas of cryo-EM maps), and guiding mutagenesis strategies to probe dynamic conformational states. We also summarize recent method extensions: AlphaFold-Multimer improves multi-chain complex assembly prediction, while molecular dynamics (MD) simulations augment AlphaFold’s static models by sampling conformational flexibility and testing stability. Despite these advances, important limitations remain—particularly for intrinsically disordered regions, protein–ligand and protein–cofactor interactions, and very large or transient assemblies—and current community benchmarks indicate that approximately one-third of residues may lack atomistic precision, underscoring uncertainty in flexible or modified segments. Framed within a clear chronological window and evidence base, our analysis highlights both the practical impact and the remaining challenges of integrating AlphaFold with experiment, outlining priorities where further methodological innovation and orthogonal validation are needed.</p></div>","PeriodicalId":793,"journal":{"name":"The Protein Journal","volume":"45 1","pages":"22 - 38"},"PeriodicalIF":1.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10930-025-10310-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145656791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peptide and Protein Tags for the Half-Life Extension of Therapeutic Agents: A Review Article","authors":"Sorour Aboutalebi,&nbsp;Fatemeh Najafi,&nbsp;Negin Yazdizadeh,&nbsp;Fatemeh Shafiee","doi":"10.1007/s10930-025-10304-6","DOIUrl":"10.1007/s10930-025-10304-6","url":null,"abstract":"<div><p>Although biological drugs have been considered as one of the effective and growing therapeutic approaches in the pharmaceutical industry in recent decades, the largest concern about them is the insufficient stability and rapid degradation in the bloodstream due to their structural nature. One of the effective methods for increasing the circulating half-life of peptide and protein drugs is the addition of half-life-extending tags, which prevent both the degradation of the biological drug and its glomerular filtration by various mechanisms, thereby increasing its half-life. This review focuses on peptide and protein tags used to enhance the pharmacokinetic profiles of biological drugs by increasing their half-life. It discusses various tags, including HSA (Human Serum Albumin), ABD (Albumin Binding Domain), DARPINS (Designed Ankyrin Repeat proteins), XTEN, CTP (Carboxy Terminal Peptide), ELP (Elastin Like Peptide), and others, and highlights both FDA-approved products and candidates currently in different stages of clinical development. In the meantime, special attention has been paid to albumin-binding domains and albumin-binding domain antibody (AlbudAb), which increases the half-life of biological drugs by binding to albumin, as the most abundant and stable protein in the body.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":793,"journal":{"name":"The Protein Journal","volume":"45 1","pages":"39 - 54"},"PeriodicalIF":1.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145650646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the Structural Stability of Recombinant Rotavirus Capsid Protein VP6 in Altered Physicochemical States Using Fluorescence and CD Spectroscopy","authors":"Modibedi Lesego Gladys,&nbsp;Preenan Pillay","doi":"10.1007/s10930-025-10307-3","DOIUrl":"10.1007/s10930-025-10307-3","url":null,"abstract":"<div><p>Rotaviruses (RV) are a major cause of severe childhood diarrhoea, particularly in developing nations, necessitating stable vaccines. Therefore, the presented preliminary study aimed to assess the impact of altered physicochemical properties on the structural stability of recombinant rotavirus capsid protein VP6 (RV-VP6). The expression system used in this study was designed by genetically engineering the RV-VP6 into <i>E. coli</i> (NiCo21(DE3))-pET28a host-vector system and purified using liquid chromatography. The purified RV-VP6 homology detection and structure prediction were conducted using LC–MS and HHpred computational analysis, which indicated a 100% probability of 1QHD_A Viral Capsid VP6 (1.95 Å), representing the crystal structure of VP6. The secondary and tertiary structural stability of RV-VP6 was evaluated in altered pH and Ca²⁺ concentrations using far UV-CD and intrinsic tryptophan fluorescence spectroscopy, respectively. The computational analysis of the far-UV CD spectra revealed a significant increase in the composition of α-helices and β-sheets in altered pH and Ca²⁺ environments compared to the denatured protein (<i>p</i> &lt; 0.0001). Intrinsic fluorescence analysis of RV-VP6 at pH 7 yielded an emission λmax of 339 nm, which shifted to 342 nm at pH 5. In 1 mM Ca²⁺, a λmax of 340 nm was observed, with an increase in intensity in 10 mM Ca²⁺, accompanied by a slight blue shift to 338 nm. Investigation of RV-VP6 under thermal stress yielded unfolding concomitant with aggregation, rendering the process irreversible and nullifying analysis using equilibrium thermodynamics. These findings form the preliminary basis for our future evaluation of manufacturing stable and enhanced RV-VP6 vaccines through the downstream process control of (1) pH, which alters the charge distribution on the surface of the protein, leading to conformational changes, and (2) Ca²⁺ ions, which interact with specific amino acid residues in the protein, thereby affecting its structure and function.</p></div>","PeriodicalId":793,"journal":{"name":"The Protein Journal","volume":"45 1","pages":"215 - 228"},"PeriodicalIF":1.4,"publicationDate":"2025-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145535065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-ionic Detergent-Assisted Refolding of Protein from Protein-SDS Complex","authors":"Teruo Akuta,&nbsp;Tomoto Ura,&nbsp;Takeshi Oikawa,&nbsp;Takashi Shibata,&nbsp;Kentaro Shiraki,&nbsp;Tsutomu Arakawa","doi":"10.1007/s10930-025-10305-5","DOIUrl":"10.1007/s10930-025-10305-5","url":null,"abstract":"<div><p>Refolding of protein from denatured structure caused by sodium dodecyl sulfate (SDS) was examined using agarose native gel electrophoresis and circular dichroism (CD). Refolding of protein from SDS complex was induced with the addition of non-ionic and zwitterionic detergents followed by agarose native gel electrophoresis. The native gel electrophoresis was done without both SDS and non-ionic detergents in the agarose gel and running buffer. The electrophoretic mobility of bovine serum albumin (BSA) drastically increased with the addition of 1% SDS to the samples indicative of SDS-BSA complex formation. The SDS-denatured BSA returned to the native mobility by the addition of non-ionic Tween 20 and Triton X-100 and zwitterionic CHAPS as a function of detergent concentration. Refolding, at least partially, was confirmed by CD, which was done in the presence of both SDS and non-ionic detergents, a condition different from the native gel electrophoresis done in their absence. When BSA was denatured by both 1% SDS and a disulfide-reducing dithiothreitol, even 10% Tween 20 was insufficient to restore the native BSA mobility on agarose native gel electrophoresis. When BSA was denatured by 1% Sarkosyl and sodium lauroyl-glutamate, Tween 20 restored the native structure at Tween 20 concentration lower than the Tween 20 concentration used for SDS denaturation. A similar refolding by non-ionic detergents was also observed for a rabbit monoclonal IgG, but not for lysozyme. The results with lysozyme suggest strong SDS binding and difficulty in dissociating the bound SDS by non-ionic detergents due to high isoelectric point of the protein and thereby more SDS binding.</p></div>","PeriodicalId":793,"journal":{"name":"The Protein Journal","volume":"45 1","pages":"185 - 196"},"PeriodicalIF":1.4,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145497777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Challenges in Serum Albumin Measurements: A Comparative Study of the Bromocresol Green and the Capillary Zone Electrophoretic Method","authors":"Mariem Othmani,&nbsp;Yessine Amri,&nbsp;Siwar Chelbi,&nbsp;Sondes Hadj Fredj,&nbsp;Taieb Messaoud,&nbsp;Rym Dabboubi","doi":"10.1007/s10930-025-10303-7","DOIUrl":"10.1007/s10930-025-10303-7","url":null,"abstract":"<div><p>Serum albumin (SA) is a key biomarker routinely used in clinical practice. Multiple analytical methods exist for its measurement, including bromocresol green (BCG) colorimetry and capillary zone electrophoresis (CZE). However, discrepancies between methods raise concerns regarding result consistency and clinical interpretation. This study aimed to compare the analytical concordance between BCG and CZE methods for SA measurement, and to assess their clinical interchangeability. A cross-sectional study conducted on 109 serum samples collected from patients undergoing serum protein electrophoresis at Bechir Hamza Children’s Hospital. SA was measured using BCG and CZE. Descriptive statistics were calculated for each method. Paired t-test and Wilcoxon signed-rank test were used to assess differences in means. Method agreement was evaluated using Passing-Bablok regression, Intraclass Correlation Coefficient (ICC), Bland–Altman plot, and a confusion matrix. BCG significantly overestimated SA compared to CZE (41.49 ± 7.30 g/L vs. 37.48 ± 6.85 g/L; p &lt; 0.001). Passing-Bablok regression revealed a regression line of y = 1.02x + 3.21, indicating a consistent positive bias. The R² value was 0.891, suggesting strong correlation. The ICC was 0.81 (95% CI 0.081–0.932), reflecting good agreement. The Bland–Altman analysis confirmed a mean difference of 4.01 g/L. Confusion matrix analysis showed perfect concordance in low albumin values but significant misclassification at higher levels, with BCG shifting many values into higher categories. While BCG and CZE methods show strong correlation, BCG consistently overestimates albumin concentrations. These findings underscore the need for method standardization and careful interpretation of results in clinical settings.</p></div>","PeriodicalId":793,"journal":{"name":"The Protein Journal","volume":"45 1","pages":"178 - 184"},"PeriodicalIF":1.4,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145497850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arginine 11, Arginine 32, and Lysine 44 of a Staphylococcal Anti-sigma Factor are Indispensable Residues","authors":"Debasmita Sinha,&nbsp;Debabrata Sinha,&nbsp;Tushar Chakraborty,&nbsp;Subrata Sau","doi":"10.1007/s10930-025-10300-w","DOIUrl":"10.1007/s10930-025-10300-w","url":null,"abstract":"<div><p>σ^B, a <i>Staphylococcus aureus</i>-encoded alternative sigma factor, is inhibited by RsbW, an anti-sigma factor. RsbW also dimerizes in solution and phosphorylates RsbV, an RsbW antagonist. Of the predicted RsbW residues involved in its dimerization and/or binding cognate factors, the roles of Arg 11, Arg 32, and Lys 44 have been demonstrated here using various tools. The structural models of three RsbW mutants, harboring Ala at positions 11, 32, and 44, were built up, and their analyses suggested that all of the above Lys/Arg residues may be involved in the dimerization of this protein. Similar analyses indicated that Lys 44 and Arg 32 may be needed for binding σ^B3, the domain 3 of σ^B. The docking studies have confirmed the roles of Arg 11 and Arg 32 in the dimerization of RsbW, and revealed that its association with σ^B3 requires Arg 32 and Lys 44. Additionally, the simulation studies proposed that all of the above Lys/Arg may be needed for its structure maintenance. To verify the computational data, three Ala-substituted RsbW mutants were also purified, and their characterization indicates that the change of Arg 11 or Lys 44 to Ala, compared to the change of Arg 32 to Ala, impacts the structure, RsbV/ σ^B3 binding affinity, and phosphorylation activity of RsbW more severely. Further, the dimerization ability of RsbW was partly affected by Ala substitution at positions 11 and 32. Jointly, Arg 11, Arg 32, and Lys 44 of RsbW are crucial residues for this σ^B inhibitor and kinase. Knowledge of crucial RsbW residues may be useful for designing antistaphylococcal drugs in the future.</p></div>","PeriodicalId":793,"journal":{"name":"The Protein Journal","volume":"45 1","pages":"197 - 214"},"PeriodicalIF":1.4,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145497855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-scale In Silico and Biochemical Evaluation of Natural Bisbenzylisoquinoline Alkaloids as Aldose Reductase Inhibitors","authors":"Emadeldin M. Kamel,&nbsp;Noha A. Ahmed,&nbsp;Sarah I. Othman,&nbsp;Adil Abalkhail,&nbsp;Faris F. Aba Alkhayl,&nbsp;Bassam A. Abuamarah,&nbsp;Saleh Maodaa,&nbsp;Al Mokhtar Lamsabhi","doi":"10.1007/s10930-025-10297-2","DOIUrl":"10.1007/s10930-025-10297-2","url":null,"abstract":"<div><p>Aldose reductase (AR) is the rate-limiting enzyme of the polyol pathway and a validated target for preventing micro- and neurovascular complications of diabetes. Here, we combined multi-scale in-silico analyses with biochemical testing to evaluate five commercially available bisbenzylisoquinoline alkaloids—cepharanthine, dauricine, isotetrandrine, fangchinoline and sinomenine—as potential AR inhibitors. Density-functional optimization, structure-based docking and 500 ns molecular-dynamics simulations revealed that the macrocyclic scaffolds of cepharanthine (ΔG_dock =  − 8.4 kcal mol⁻¹) and dauricine (− 9.7 kcal mol⁻¹) fully occupy the Phe122-Trp219-Trp111 aromatic cage and lock AR into a single, deep free-energy basin, whereas sinomenine explores a broad landscape. MM/PBSA calculations on the 150–200 ns of each trajectory ranked binding free energies as dauricine ≈ isotetrandrine ≈ cepharanthine &lt; sinomenine &lt; fangchinoline, with van-der-Waals forces dominating. ADMET profiling predicted high gastrointestinal absorption across the series but flagged a potential hERG potassium-channel liability for the four macrocycles. Enzyme-kinetic assays corroborated the computational hierarchy: cepharanthine, dauricine and isotetrandrine inhibited recombinant AR with IC₅₀ values of 4.25 ± 0.42, 5.38 ± 0.22 and 6.65 ± 0.40 µM, respectively, compared with 2.36 ± 0.32 µM for quercetin. Lineweaver–Burk and Michaelis–Menten analysis showed mixed inhibition for cepharanthine (<i>K</i>_i = 3.71 µM) and non-competitive inhibition for dauricine (<i>K</i>_i = 4.63 µM) and isotetrandrine (<i>K</i>_i = 6.99 µM). Fangchinoline and sinomenine were an order of magnitude weaker (IC₅₀ = 37–57 µM). Taken together, these data position cepharanthine and dauricine as mechanistically validated, hit-stage starting points for next-generation AR inhibitors, and identify isotetrandrine as an allosteric back-up scaffold. More broadly, the study illustrates a transparent, reproducible computational–experimental workflow for prioritizing structurally complex natural products against redox enzymes implicated in diabetic pathology.</p></div>","PeriodicalId":793,"journal":{"name":"The Protein Journal","volume":"45 1","pages":"125 - 145"},"PeriodicalIF":1.4,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Strategic Approaches for Overcoming Peptide and Protein Drug Limitations","authors":"Mahsa Cheshomi,&nbsp;Nikta Shobeiri,&nbsp;Amineh Sadat Tajani,&nbsp;Bahman Khameneh","doi":"10.1007/s10930-025-10302-8","DOIUrl":"10.1007/s10930-025-10302-8","url":null,"abstract":"<div><p>Protein and peptide drugs have become essential in treating numerous diseases due to their high specificity and therapeutic potential. However, their clinical application faces several challenges, including chemical instability, physical instability, short in vivo half-life, low oral bioavailability, and immunogenicity. These issues reduce drug efficacy and limit patient compliance. This review critically examines these limitations and presents current strategies to address them. PEGylation, the covalent or noncovalent attachment of polyethylene glycol (PEG) molecules to proteins, is highlighted for its ability to increase stability, reduce renal clearance, lower immunogenicity, and extend half-life. The review distinguishes between random and site-specific PEGylation, highlighting site-specific methods that preserve protein activity while optimizing pharmacokinetics. Additionally, the encapsulation of proteins in polymeric and lipid-based delivery systems is discussed to protect drugs from enzymatic degradation, control their release, and enhance absorption. Biobetter approaches, including site-directed mutagenesis, are also presented to improve protein stability and reduce immunogenicity. Market data and approved drug examples illustrate the impact of these strategies. Overall, the article provides a comprehensive overview of innovative pharmaceutical and biotechnological methods that enhance the clinical performance and market viability of protein therapeutics.</p></div>","PeriodicalId":793,"journal":{"name":"The Protein Journal","volume":"45 1","pages":"8 - 21"},"PeriodicalIF":1.4,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}