Drug Development Research最新文献

{"title":"Imidazolidine-Based Aspartate Inhibitors for Candida Infections","authors":"B. Bindu,&nbsp;A. Manikandan,&nbsp;S. Jeevitha,&nbsp;Joe Jacob Kunju,&nbsp;S. Vijayalakshmi","doi":"10.1002/ddr.70074","DOIUrl":"https://doi.org/10.1002/ddr.70074","url":null,"abstract":"<div>\u0000 \u0000 <p>The fungal infection gradually poses a life threat to mankind, candidiasis caused by Candida sp. is one among them. We describe the aspartate protease inhibition potentials of 12 sulfonyl-containing imidazolidines (<b>5a-l</b>) anti-candidal agents. <i>Candida Albicans</i> secretes aspartic proteases (Saps), one of its most important virulent agents. These hydrolytic enzymes are critical for both fungal physiological processes and host-fungus interactions. Compounds <b>5a-l</b> were examined for their fungal aspartate protease inhibition apart from their anti-candida activity. These findings were equipped and validated in silico using molecular docking and in vitro enzyme inhibition assays. The study found that imidazolidine derivatives inhibited aspartic protease and exhibited anti-candida action. Conclusively, imidazolidines <b>5g, 5h,</b> and <b>5j</b> were perceived as the most potent anti-candida compounds and are presently being evaluated for their preclinical studies.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 2","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel 3-Substituted-2H-Chromene Scaffold Based Fluorinated Hydrophobic Fragment as In-Vitro Antiproliferative Agents and Apoptosis Inducers Targeting Both VEGFR-2/BRAFV600E and h-DHFR With Molecular Docking Simulation","authors":"Mohamed A. Salem,&nbsp;Moustafa S. Abusaif,&nbsp;Nirvana A. Gohar,&nbsp;Yousry A. Ammar,&nbsp;Ahmed Ragab","doi":"10.1002/ddr.70085","DOIUrl":"https://doi.org/10.1002/ddr.70085","url":null,"abstract":"<div>\u0000 \u0000 <p>Recently, there has been an increasing interest in the use of protein kinase inhibitors as a therapeutic strategy for the treatment of cancer. In this study, a new series of 2<i>H</i>-chromene derivatives (<b>2</b>-<b>5</b> and <b>6</b>-<b>8</b>) and 3<i>H</i>-benzo[<i>f</i>]chromene carbohydrazide derivative (<b>9</b>) were synthesized. The structure of the designed derivatives was characterized by IR, ¹H/¹³C NMR, and elemental analysis. Moreover, the cytotoxic activity of the newly synthesized chromenes was evaluated against breast cancer cell lines (MDA-MB-231 and MCF-7) and a cervical cancer cell line (HeLa). The results of these evaluations demonstrated promising activity, ranging from good to moderate. Additionally, the lung fibroblast cell line (WI-38), as a normal cell line, was also utilized to assess the active derivatives' selectivity. Among the compounds tested, chromene derivative <b>3</b> demonstrated the highest potency, exhibiting IC₅₀ values of 5.36 ± 0.50, 7.82 ± 0.60, and 9.28 ± 0.70 µM against the MDA-MB 231, MCF-7, and HeLa cell lines, respectively. The potential of chromone <b>3</b> as a multi-targeted anticancer agent was assessed by evaluating its activity against BRAF and VEGFR-2. Notably, the most promising chromene derivative <b>3</b> demonstrated significant VEGFR2 activity with an IC₅₀ value of 0.224 µM compared to sorafenib's 0.045 µM, while exhibiting inhibitory activity against BRAF with an IC₅₀ value of 1.695 µM relative to Vemurafenib's IC₅₀ value of 0.468 µM. In addition, compound <b>3</b> inhibits the DHFR enzyme with an IC₅₀ value of 2.217 ± 0.014 µM, compared to methotrexate (IC₅₀ = 0.4315 ± 0.019 µM). These results revealed that the compound has multifaceted mechanisms of action that may augment its therapeutic effectiveness. In addition, compound <b>3</b> causes overexpression of caspase-3 and Bax by 6.13 and 8.85-fold, respectively. It also downregulates the antiapoptotic Bcl-2 level by 0.4775-fold compared to the untreated MDA-MB 231 cells. Flow cytometry analysis of MDA-MB-231 cells indicates that compound 3 induces cell cycle arrest in the G0-G1 phase, with an observed percentage of 73.15%. The in-silico toxicity prediction was evaluated and demonstrated a good toxicity profile. Finally, molecular docking studies supported these findings by confirming strong binding affinities of the derivatives to VEGFR-2, BRAF, and DHFR.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 2","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143717187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carboxymethyl Starch: A Contemporary Paradigm for Anti Cancer Drug Delivery","authors":"Rabab Fatima","doi":"10.1002/ddr.70082","DOIUrl":"https://doi.org/10.1002/ddr.70082","url":null,"abstract":"<div>\u0000 \u0000 <p>Carboxymethyl starch (CMS) represents a significant advancement in addressing the multifaceted challenges of anticancer drug delivery, including poor aqueous solubility, nonspecific biodistribution, and premature drug release. The strategic incorporation of carboxymethyl moiety (-CH₂COOH) onto the starch backbone confers a suite of physicochemical properties that markedly enhance its efficacy as a drug carrier. The carboxymethyl groups, with a pKa of approximately 4.5, exhibit pronounced pH-responsiveness, undergoing a transition from a predominantly deprotonated, hydrophilic state at physiological pH (7.4) to a more protonated form in the acidic tumor microenvironment (pH 6.5–6.8) facilitating targeted drug release at neoplastic site. The mucoadhesive attributes ascribable to carboxyl-mucin interactions, prolong gastrointestinal residence time for oral formulations, optimizing drug absorption. Furthermore, these functional groups serve as reactive sites for subsequent modifications, facilitating the development of multifunctional, targeted drug delivery systems with enhanced biocompatibility and minimized off-target effects. The versatility and biocompatibility of CMS position it as a promising platform for next-generation anticancer therapeutics, offering potential for significant advancements in oncological treatment modalities.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 2","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of Steroidogenesis in Prostate Cancer Cells by Both a Natural and Another Synthetic Steroid","authors":"Marisa Cabeza,&nbsp;Karla Mejía,&nbsp;Fernando García,&nbsp;Ivonne Heuze,&nbsp;Miguel Morales,&nbsp;Mauricio Rodríguez-Dorantes","doi":"10.1002/ddr.70078","DOIUrl":"https://doi.org/10.1002/ddr.70078","url":null,"abstract":"<p>Studies suggest that vegetarians and Asians have lower mortality rates from prostate cancer compared to men who follow a Western diet. β-sitosterol, a key compound of plant-based diets, has been found to induce significant changes in the ultrasonic structure of the prostatic adenomas, making it a promising candidate for further prostate cancer research. Consequently, we investigated the potential of β-sitosterol and the synthetic derivative <b>2</b> as potent inhibitors of androgen synthesis, a critical process for the growth and survival of prostate tumor LNCaP cells. Solubilized LNCaP microsomes were used as a source of SRD5A1 and AKR1C3 to monitor androgen synthesis from labeled androstenedione, both in the presence and absence of β-sitosterol or <b>2</b>. Furthermore, the effect of these steroids on LNCaP viability was determined using the MTT method. Our findings revealed significant insights into the androgen synthesis pathways in LNCaP cells. The most efficient metabolic route for dihydrotestosterone formation was the conversion of androstenedione to 5α-androstanedione rather than from testosterone in LNCaP. This conclusion is supported by the Vmax values for 5α-androstanedione formation (271.05 ± 5.0 ng/mg protein/min) and the Vmax of testosterone formation (80.1 ± 8.0 ng/mg protein/min). Both β-sitosterol and <b>2</b> demonstrated substantial inhibitory effects of these enzymes for dihydrotestosterone formation and significantly reduced cell viability, highlighting their therapeutic potential. These findings enhance our understanding of the inhibitory effects of β-sitosterol and <b>2</b> on LNCaP cells and suggest their promising application in the treatment of prostate cancer.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 2","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.70078","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143689922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Synthesis and Anti-Influenza Virus Activity of 4-Tert-Butyl-N-(3-Oxo-1-Thia-4-Azaspiro[4.5]Dec-4-yl)Benzamide Derivatives That Target Hemagglutinin-Mediated Fusion","authors":"Gözde Çınar,&nbsp;Zeynep Alikadıoğlu,&nbsp;Özge Soylu-Eter,&nbsp;Lieve Naesens,&nbsp;Gökçe Cihan-Üstündağ","doi":"10.1002/ddr.70080","DOIUrl":"https://doi.org/10.1002/ddr.70080","url":null,"abstract":"<p>Hemagglutinin (HA) is a viral glycoprotein that mediates influenza virus entry into the host cell and is considered a relevant viral target. We here report the identification of a class of 4-<i>tert</i>-butylphenyl-substituted spirothiazolidinones as HA-mediated fusion inhibitors with specific activity against influenza A/H3N2 virus. The novel spirocyclic compounds were achieved by using one-pot cyclocondensation method and the chemical structures were characterized by IR, ¹H NMR, ¹³C NMR, and elemental analysis. Compound <b>2c</b>, bearing methyl substitutions at positions 2- and 8- of the spiro ring displayed an EC₅₀ value against influenza A/H3N2 virus of 1.3 μM and an antiviral selectivity index of 30. The fusion-inhibiting effect of compound <b>2c</b> was revealed in the polykaryon assay which is based on cell-cell fusion when influenza virus H3 HA-transfected cells are exposed to low pH. Computer-aided docking was performed to predict the possible binding pocket in the H3 HA trimer. Resistance data and <i>in silico</i> studies indicated that compound <b>2c</b> has an overlapping binding pocket in the stem region of H3 HA with the known fusion inhibitors TBHQ and arbidol.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 2","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.70080","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143689447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Benzosuberone/Indanone-Linked Thiazoles as Small-Molecule SARS-CoV-2 Main Protease Inhibitors","authors":"Thoraya A. Farghaly,&nbsp;Elham N. Bifari,&nbsp;Mariam A. Al-sheikh,&nbsp;Afaf Y. Khormi,&nbsp;Hanadi Y. Medrasi,&nbsp;Jihan Qurban,&nbsp;Hanan Gaber Abdulwahab","doi":"10.1002/ddr.70081","DOIUrl":"10.1002/ddr.70081","url":null,"abstract":"<div>\u0000 \u0000 <p>Herein, novel benzosuberone/indanone-linked thiazoles were designed and synthesized as small-molecule SARS-CoV-2 Main protease (M^pro) inhibitors with potential anti-COVID activity. All thiazole derivatives were synthesized from the reaction of thiosemicarbazone derivatives with α-halocarbonyl derivatives. The structures of novel benzosuberone/indanone-linked thiazoles were confirmed based on their spectral data. Thiazolyl-benzosuberone <b>9d</b> and thiazolyl-indanone <b>14</b> were the most potent against M^pro displaying one-digit IC₅₀ values of 5.94 and 8.47 µM, respectively, compared to ritonavir (IC₅₀ = 2.4 µM). Moreover, antiviral assay revealed the ability of compounds <b>9d</b> and <b>14</b> to inhibit the replication of SARS-CoV-2 in Vero cells at EC₅₀ values of 9.33 and 28.75 µM, respectively, relative to ritonavir (EC₅₀ = 1.72 µM). Cytotoxicity assay in Vero cells was also conducted. <b>9d</b> and <b>14</b> showed CC₅₀ values of 289.63 and 229.42 µM and SI of 31.0 and 7.9, respectively. In addition, a docking study revealed proper orientation and well-fitting of title compounds into the binding pocket of SARS-CoV-2 M^pro.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 2","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Panaxadiol Attenuates Brain Damage by Inhibiting Ferroptosis in a Rat Model of Cerebral Hemorrhage","authors":"Min Zhao,&nbsp;Yu Wang,&nbsp;Jing Li,&nbsp;Quan Wen,&nbsp;Yue Liu,&nbsp;Yanan Zhao","doi":"10.1002/ddr.70079","DOIUrl":"10.1002/ddr.70079","url":null,"abstract":"<div>\u0000 \u0000 <p>Intracerebral hemorrhage (ICH) is the most common subtype of hemorrhage stroke, with a high disability, morbidity and mortality rate globally. Panaxadiol (PD), a triterpenoid sapogenin monomer, is isolated from the roots of ginseng, which has shown a variety of biological properties, such as anti-inflammation, anti-cancer, and neuroprotection. However, its effect and mechanism on ICH were still unknown. Thirty-six rats were randomly divided into six group (<i>n</i> = 6), namely, sham, ICH, ICH + 5 mg/kg PD, ICH + 10 mg/kg PD, ICH + 20 mg/kg PD, and ICH + 10 mg/kg PD + 50 mg/kg vismodegib. Rats were treated with type IV collagenase to induce an in vivo model of ICH, and then intraperitoneally injected with PD (5, 10 and 20 mg/kg) and 50 mg/kg vismodegib (an inhibitor of hedgehog signal). The effect and potential mechanism of PD on ICH were explored by behavioral test, brain water content measurement, Evans blue detection, hematoxylin-eosin (HE) staining, iron level examination, Prussian blue staining, western blot and immunohistochemistry, respectively. An increase in the mNSS (13.17 ± 1.17), and a decrease in the rotarod latency (40.67 ± 9.31), modified Garcia score (9.83 ± 1.47), forelimb use times (3.33 ± 0.82), left forepaw placements (29.90 ± 4.38) and left turns (17.34 ± 3.55) in ICH rats were reversed with the PD treatment (6.83 ± 0.75, 113.5 ± 11.95, 17.50 ± 1.87, 8.17 ± 0.98, 63.56 ± 9.84, and 42.13 ± 4.52 respectively). PD treatment reduced the brain water content (73.13 ± 3.16 vs. 86.82 ± 4.74), the level of Evans blue (2.14 ± 0.25 vs. 4.03 ± 0.20) and cerebral hemorrhage in ICH rats. Also, PD injection decreased the iron level (0.06 ± 0.005 vs. 0.17 ± 0.02) and the expression of ACSL4 (0.56 ± 0.07 vs. 1.23 ± 0.16), with the increased expression of GPX4 (1.14 ± 0.08 vs. 0.21 ± 0.03) in ICH rats. Mechanically, PD treatment restored the decreased expression of SHH (0.96 ± 0.13 vs. 0.20 ± 0.03), GLI1 (0.89 ± 0.13 vs. 0.06 ± 0.007) and PTCH (0.75 ± 0.05 vs. 0.10 ± 0.01) in ICH rats. Inhibition of SHH signaling by vismodegib reversed the ameliorative effect of PD on ICH rats. PD improved brain damage by suppressing ferroptosis via the activation of the SHH/GLI signaling pathway, which could lay a theoretical foundation for the treatment of ICH.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 2","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Topical Compound Gel Loading Minoxidil and Tofacitinib for Treatment of Alopecia Areata: Formulation, Characterization, and In Vitro/In Vivo Evaluation","authors":"Rui Wang,&nbsp;Ying Zhou,&nbsp;Peng Yang,&nbsp;Hailong Zhang,&nbsp;Jinsong Ding","doi":"10.1002/ddr.70076","DOIUrl":"https://doi.org/10.1002/ddr.70076","url":null,"abstract":"<div>\u0000 \u0000 <p>Although topical minoxidil is the most common drug for alopecia areata (AA), it has limited therapeutic effect in the treatment of patients with moderate and severe AA because it can only promote hair follicle growth and improve the characteristics of hair follicle degeneration in AA and cannot alleviate local inflammatory response. Therefore, we designed a novel topical compound gel loading minoxidil and Janus kinases (JAK) inhibitors tofacitinib. The compound gel not only had good semi-solid properties and the effect of permeation but also maintained stability for up to 3 months under accelerated conditions, ensuring the long-term quality of the formulation. This compound gel can effectively improve hair follicle growth and significantly alleviate local inflammatory response by downregulation of the ratio of inflammatory factor interferon-γ to anti-inflammatory factor interleukin-4 in C3H/HeN mice bearing AA, achieving the purpose of synergistic treatment of AA. The first combination of minoxidil and tofacitinib in a topical formulation gives a new idea for the clinical treatment of AA.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 2","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143645812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Innovative Multitarget Organoselenium Hybrids With Apoptotic and Anti-Inflammatory Properties Acting as JAK1/STAT3 Suppressors","authors":"Saad Shaaban,&nbsp;Aya Yaseen Mahmood Alabdali,&nbsp;Mai H. A. Mousa,&nbsp;Hussein Ba-Ghazal,&nbsp;Yasair S. Al-Faiyz,&nbsp;Ibrahim Elghamry,&nbsp;Hanan A. Althikrallah,&nbsp;Arwa Omar Al Khatib,&nbsp;Mohamed Alaasar,&nbsp;Ahmed A. Al-Karmalawy","doi":"10.1002/ddr.70075","DOIUrl":"https://doi.org/10.1002/ddr.70075","url":null,"abstract":"<div>\u0000 \u0000 <p>Herein, we report the design, synthesis, and characterization of novel organoselenium (OSe) hybrids (<b>5</b>–<b>19</b>) via modifications of the lead, <i>N</i>-(4-selaneylphenyl)-2-selaneylacetamide. The OSe-based thiazol <b>9</b> showed the highest growth inhibition % (GI%) of 64.72% relative to the positive reference doxorubicin (DOX), with a GI% of 79.5%. Furthermore, the novel OSe derivatives showed low GI% values compared to the normal cell lines employed, demonstrating their selectivity. The OSe tethered <i>N</i>-chloroacetamide <b>5</b> and Schiff base <b>19</b> showed a cytotoxic effect with an IC₅₀ of (25.07 and 11.61 µM), respectively, against the A549 tumor cell line and IC₅₀ of (34.22 and 20.12 µM), respectively, against the HELA cancer cell line. Enzyme-linked immunosorbent assay to study the JAK1 and the STAT3 inhibitory potentials of OSe compounds <b>5</b> and <b>19</b> in the A549 cancer cells both showed promising inhibitory activities with IC₅₀ values of 25.07 and 11.61 µM, respectively. Protein expression analysis on the A549 cancer cell line on OSe compounds <b>5</b> and <b>19</b> showed upregulation of P53, BAX, and Caspases 3, 6, 8, and 9 as apoptotic proteins. However, both candidates expressed downregulation of the antiapoptotic proteins (BCL2, MMP2, and MMP9). Moreover, OSe compounds <b>5</b> and <b>19</b> described the downregulation of the examined inflammatory proteins: COX2, IL-6, and IL-1β. In addition, OSe compound <b>19</b> showed potential cell cycle arrest at the G0, S, and G2-M layers, with an increase in cellular levels. Finally, molecular docking studies of OSe compound <b>19</b> showed the most promising inhibitory potential toward the JAK1 and STAT3 target receptors, with binding scores and interactions exceeding that of the cocrystallized inhibitor of JAK1.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 2","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143645814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Strategies for the Discovery and Design of Tissue Plasminogen Activators: Insights Into Bioengineering Objectives","authors":"Amirhossein Akbarpour Arsanjani,&nbsp;Davood Rabiei Faradonbeh,&nbsp;Ziba Veisi Malekshahi,&nbsp;Bashir Mosayyebi,&nbsp;Babak Negahdari","doi":"10.1002/ddr.70072","DOIUrl":"https://doi.org/10.1002/ddr.70072","url":null,"abstract":"<div>\u0000 \u0000 <p>Tissue plasminogen activators (tPAs) are critical in fibrinolysis and have become central to treating thrombotic disorders, including heart attacks, strokes, and pulmonary embolisms. Despite their efficacy, challenges such as bleeding complications, limited fibrin specificity, and rapid clearance necessitate the discovery of novel tPAs and the engineering of improved variants. This review highlights strategies for the discovery of tPAs from natural sources, including human, bacterial, venom-derived, and bat saliva-derived agents, as well as enzyme engineering approaches that enhance functional characteristics such as half-life, fibrin specificity, resistance to inhibitors, and clot penetration. Furthermore, this review explores alternative therapeutic approaches independent of tPAs, focusing on nonplasminogen activator agents and strategies that target platelets. By addressing current challenges and identifying future opportunities, this review provides a comprehensive perspective on advancing thrombolytic therapies through innovative discovery and design strategies.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 2","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}