{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T22:28:56Z","timestamp":1789511336936,"version":"build-2803163510"},"reference-count":128,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,6,6]],"date-time":"2024-06-06T00:00:00Z","timestamp":1717632000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Phenotypic drug discovery (PDD) involves screening compounds for their effects on cells, tissues, or whole organisms without necessarily understanding the underlying molecular targets. PDD differs from target-based strategies as it does not require knowledge of a specific drug target or its role in the disease. This approach can lead to the discovery of drugs with unexpected therapeutic effects or applications and allows for the identification of drugs based on their functional effects, rather than through a predefined target-based approach. Ultimately, disease definitions are mostly symptom-based rather than mechanism-based, and the therapeutics should be likewise. In recent years, there has been a renewed interest in PDD due to its potential to address the complexity of human diseases, including the holistic picture of multiple metabolites engaging with multiple targets constituting the central hub of the metabolic host\u2013microbe interactions. Although PDD presents challenges such as hit validation and target deconvolution, significant achievements have been reached in the era of big data. This article explores the experiences of researchers testing the effect of a thymic peptide hormone, thymosin alpha-1, in preclinical and clinical settings and discuss how its therapeutic utility in the precision medicine era can be accommodated within the PDD framework.<\/jats:p>","DOI":"10.3389\/fmed.2024.1388959","type":"journal-article","created":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T19:26:41Z","timestamp":1718134001000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Phenotypic drug discovery: a case for thymosin alpha-1"],"prefix":"10.3389","volume":"11","author":[{"given":"Enrico","family":"Garaci","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Paci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Matteucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Costantini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Puccetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigina","family":"Romani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,6,6]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.mib.2019.10.008","article-title":"Antibiotics: past, present and future","volume":"51","author":"Hutchings","year":"2019","journal-title":"Curr Opin Microbiol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/978-1-60761-244-5_1","article-title":"An historical overview of drug discovery","volume":"572","author":"Pina","year":"2009","journal-title":"Methods Mol Biol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1038\/nrd3480","article-title":"How were new medicines discovered?","volume":"10","author":"Swinney","year":"2011","journal-title":"Nat Rev Drug Discov"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.1177\/1087057113506118","article-title":"Neoclassic drug discovery: the case for lead generation using phenotypic and functional approaches","volume":"18","author":"Lee","year":"2013","journal-title":"J Biomol Screen"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1038\/nrd.2017.111","article-title":"Opportunities and challenges in phenotypic drug discovery: an industry perspective","volume":"16","author":"Moffat","year":"2017","journal-title":"Nat Rev Drug Discov"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1038\/s41573-022-00472-w","article-title":"Phenotypic drug discovery: recent successes, lessons learned and new directions","volume":"21","author":"Vincent","year":"2022","journal-title":"Nat Rev Drug Discov"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"852143","DOI":"10.3389\/fphar.2022.852143","article-title":"Recent advances in Cancer drug discovery through the use of phenotypic reporter systems, connectivity mapping, and pooled CRISPR screening","volume":"13","author":"Salame","year":"2022","journal-title":"Front Pharmacol"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1093\/qjmed\/hcq057","article-title":"Medical reductionism: lessons from the great philosophers","volume":"103","author":"Beresford","year":"2010","journal-title":"QJM"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"5727","DOI":"10.1021\/acs.jcim.0c00861","article-title":"What are the odds of finding a COVID-19 drug from a lab repurposing screen?","volume":"60","author":"Edwards","year":"2020","journal-title":"J Chem Inf Model"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"101487","DOI":"10.1016\/j.isci.2020.101487","article-title":"Mechanism of action and target identification: a matter of timing in drug discovery","volume":"23","author":"Davis","year":"2020","journal-title":"iScience"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1016\/j.jmb.2015.09.030","article-title":"In situ Cryo-Electron tomography: a post-reductionist approach to structural biology","volume":"428","author":"Asano","year":"2016","journal-title":"J Mol Biol"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"61","DOI":"10.3390\/ph11030061","article-title":"Proximal pathway enrichment analysis for targeting comorbid diseases via network endopharmacology","volume":"11","author":"Aguirre-Plans","year":"2018","journal-title":"Pharmaceuticals (Basel)"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1177\/1535370218794365","article-title":"The inadequacy of the reductionist approach in discovering new therapeutic agents against complex diseases","volume":"243","author":"Duval","year":"2018","journal-title":"Exp Biol Med (Maywood)"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"12651","DOI":"10.1021\/acs.jmedchem.2c01737","article-title":"Is target-based drug discovery efficient? Discovery and \"off-target\" mechanisms of all drugs","volume":"66","author":"Sadri","year":"2023","journal-title":"J Med Chem"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1257601","DOI":"10.1126\/science.1257601","article-title":"Disease networks. Uncovering disease-disease relationships through the incomplete interactome","volume":"347","author":"Menche","year":"2015","journal-title":"Science"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"9","DOI":"10.3389\/fphys.2010.00009","article-title":"What is systems biology?","volume":"1","author":"Breitling","year":"2010","journal-title":"Front Physiol"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"637999","DOI":"10.3389\/fphys.2021.637999","article-title":"History and future perspectives on the discipline of quantitative systems pharmacology modeling and its applications","volume":"12","author":"Azer","year":"2021","journal-title":"Front Physiol"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.tips.2005.02.007","article-title":"The efficiency of multi-target drugs: the network approach might help drug design","volume":"26","author":"Csermely","year":"2005","journal-title":"Trends Pharmacol Sci"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1146","DOI":"10.1016\/j.drudis.2020.05.010","article-title":"Systems biology approach for studying neurodegenerative diseases","volume":"25","author":"Lam","year":"2020","journal-title":"Drug Discov Today"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/s41581-023-00705-0","article-title":"Network medicine: an approach to complex kidney disease phenotypes","volume":"19","author":"Pandey","year":"2023","journal-title":"Nat Rev Nephrol"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1038\/nbt1007-1110","article-title":"Network pharmacology","volume":"25","author":"Hopkins","year":"2007","journal-title":"Nat Biotechnol"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1039\/C5NP00005J","article-title":"Network pharmacology applications to map the unexplored target space and therapeutic potential of natural products","volume":"32","author":"Kibble","year":"2015","journal-title":"Nat Prod Rep"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"851","DOI":"10.3389\/fendo.2019.00851","article-title":"Editorial: metformin: beyond diabetes","volume":"10","author":"Bost","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1700048","DOI":"10.1002\/minf.201700048","article-title":"Network-based approaches in pharmacology","volume":"36","author":"Boezio","year":"2017","journal-title":"Mol Inform"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1038\/nchembio.118","article-title":"Network pharmacology: the next paradigm in drug discovery","volume":"4","author":"Hopkins","year":"2008","journal-title":"Nat Chem Biol"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"e1002820","DOI":"10.1371\/journal.pcbi.1002820","article-title":"Chapter 5: network biology approach to complex diseases","volume":"8","author":"Cho","year":"2012","journal-title":"PLoS Comput Biol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1016\/j.drudis.2017.12.001","article-title":"Network-based technologies for early drug discovery","volume":"23","author":"Fotis","year":"2018","journal-title":"Drug Discov Today"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1016\/j.phrs.2016.06.018","article-title":"Network pharmacology of cancer: from understanding of complex interactomes to the design of multi-target specific therapeutics from nature","volume":"111","author":"Poornima","year":"2016","journal-title":"Pharmacol Res"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1016\/S0021-9258(17)37900-0","article-title":"The chemistry and biology of thymosin. I. Isolation, characterization, and biological activities of thymosin alpha1 and polypeptide beta1 from calf thymus","volume":"254","author":"Low","year":"1979","journal-title":"J Biol Chem"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1073\/pnas.56.3.1010","article-title":"Preparation, assay, and partial purification of a thymic lymphocytopoietic factor (thymosin)","volume":"56","author":"Goldstein","year":"1966","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1517\/14712590902911412","article-title":"From lab to bedside: emerging clinical applications of thymosin alpha 1","volume":"9","author":"Goldstein","year":"2009","journal-title":"Expert Opin Biol Ther"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1196\/annals.1415.039","article-title":"Thymosin alpha1: a historical overview","volume":"1112","author":"Garaci","year":"2007","journal-title":"Ann N Y Acad Sci"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"S117","DOI":"10.1517\/14712598.2015.1033393","article-title":"Historical review of thymosin \u03b1 1 in infectious diseases","volume":"15","author":"Camerini","year":"2015","journal-title":"Expert Opin Biol Ther"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1016\/j.bioorg.2019.04.003","article-title":"Antioxidant and angiotensin-converting enzyme (ACE) inhibitory activity of thymosin alpha-1 (Th\u03b11) peptide","volume":"87","author":"Kharazmi-Khorassani","year":"2019","journal-title":"Bioorg Chem"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"48","DOI":"10.31083\/j.fbl2702048","article-title":"Thymosin-\u03b11 binds with ACE and downregulates the expression of ACE2 in human respiratory epithelia","volume":"27","author":"Zhang","year":"2022","journal-title":"Front Biosci (Landmark Ed)"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/S1567-5769(01)00139-4","article-title":"Involvement of mitogen-activated protein kinases in the signal transduction pathway of bone marrow-derived macrophage activation in response to in vitro treatment with thymosin alpha 1","volume":"2","author":"Sodhi","year":"2002","journal-title":"Int Immunopharmacol"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1007\/s10495-015-1138-9","article-title":"Thymosin alpha 1 suppresses proliferation and induces apoptosis in breast cancer cells through PTEN-mediated inhibition of PI3K\/Akt\/mTOR signaling pathway","volume":"20","author":"Guo","year":"2015","journal-title":"Apoptosis"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1038\/sj.embor.7400433","article-title":"Activation of IKK by thymosin alpha1 requires the TRAF6 signalling pathway","volume":"6","author":"Zhang","year":"2005","journal-title":"EMBO Rep"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1749-6632.2012.06716.x","article-title":"Jack of all trades: thymosin \u03b11 and its pleiotropy","volume":"1269","author":"Romani","year":"2012","journal-title":"Ann N Y Acad Sci"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1002\/1521-4141(200003)30:3<778::AID-IMMU778>3.0.CO;2-I","article-title":"Thymosin-alpha1 regulates MHC class I expression in FRTL-5 cells at transcriptional level","volume":"30","author":"Giuliani","year":"2000","journal-title":"Eur J Immunol"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"7255","DOI":"10.2147\/OTT.S177943","article-title":"Thymosin \u03b11 suppresses migration and invasion of PD-L1 high-expressing non-small-cell lung cancer cells via inhibition of STAT3-MMP2 signaling","volume":"11","author":"Bo","year":"2018","journal-title":"Onco Targets Ther"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/0162-3109(96)00131-2","article-title":"Thymosin alpha 1 interacts with the VIP receptor-effector system in rat and mouse immunocompetent cells","volume":"34","author":"Pozo","year":"1996","journal-title":"Immunopharmacology"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"110113","DOI":"10.1016\/j.intimp.2023.110113","article-title":"Thymosin \u03b11 interacts with Galectin-1 modulating the \u03b2-galactosides affinity and inducing alteration in the biological activity","volume":"118","author":"Matteucci","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1007\/s00726-016-2169-4","article-title":"New studies about the insertion mechanism of Thymosin \u03b11 in negative regions of model membranes as starting point of the bioactivity","volume":"48","author":"Mandaliti","year":"2016","journal-title":"Amino Acids"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"1462","DOI":"10.1021\/acs.biochem.5b01345","article-title":"Thymosin \u03b11 interacts with exposed phosphatidylserine in membrane models and in cells and uses serum albumin as a carrier","volume":"55","author":"Mandaliti","year":"2016","journal-title":"Biochemistry"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"1843","DOI":"10.3390\/molecules22111843","article-title":"Thymosin \u03b11 interacts with hyaluronic acid electrostatically by its terminal sequence LKEKK","volume":"22","author":"Mandaliti","year":"2017","journal-title":"Molecules"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"2265","DOI":"10.1182\/blood-2006-02-004762","article-title":"Thymosin alpha1 activates dendritic cell tryptophan catabolism and establishes a regulatory environment for balance of inflammation and tolerance","volume":"108","author":"Romani","year":"2006","journal-title":"Blood"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"4232","DOI":"10.1182\/blood-2003-11-4036","article-title":"Thymosin alpha 1 activates dendritic cells for antifungal Th1 resistance through toll-like receptor signaling","volume":"103","author":"Romani","year":"2004","journal-title":"Blood"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1093\/intimm\/dxm097","article-title":"Thymosin alpha1 activates the TLR9\/MyD88\/IRF7-dependent murine cytomegalovirus sensing for induction of anti-viral responses in vivo","volume":"19","author":"Bozza","year":"2007","journal-title":"Int Immunol"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1002\/tox.22765","article-title":"Thymosin alpha-1; a natural peptide inhibits cellular proliferation, cell migration, the level of reactive oxygen species and promotes the activity of antioxidant enzymes in human lung epithelial adenocarcinoma cell line (A549)","volume":"34","author":"Kharazmi-Khorassani","year":"2019","journal-title":"Environ Toxicol"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"1237978","DOI":"10.3389\/fimmu.2023.1237978","article-title":"Mechanism and clinical application of thymosin in the treatment of lung cancer","volume":"14","author":"Liu","year":"2023","journal-title":"Front Immunol"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1038\/nm.4305","article-title":"Thymosin \u03b11 represents a potential potent single-molecule-based therapy for cystic fibrosis","volume":"23","author":"Romani","year":"2017","journal-title":"Nat Med"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1080\/14712598.2018.1484103","article-title":"Cellular proteostasis: a new twist in the action of thymosin \u03b11","volume":"18","author":"Stincardini","year":"2018","journal-title":"Expert Opin Biol Ther"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"112921","DOI":"10.1016\/j.ejmech.2020.112921","article-title":"Thymosin alpha 1 exerts beneficial extrapulmonary effects in cystic fibrosis","volume":"209","author":"Bellet","year":"2021","journal-title":"Eur J Med Chem"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.1073\/pnas.81.5.1391","article-title":"Distribution of prothymosin alpha in rat tissues","volume":"81","author":"Haritos","year":"1984","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"1731","DOI":"10.1016\/S0196-9781(98)00132-6","article-title":"The conformation of peptide thymosin alpha 1 in solution and in a membrane-like environment by circular dichroism and NMR spectroscopy. A possible model for its interaction with the lymphocyte membrane","volume":"19","author":"Grottesi","year":"1998","journal-title":"Peptides"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1080\/14712598.2018.1456527","article-title":"Potential mechanism of thymosin-\u03b11-membrane interactions leading to pleiotropy: experimental evidence and hypotheses","volume":"18","author":"Mandaliti","year":"2018","journal-title":"Expert Opin Biol Ther"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"S71","DOI":"10.1517\/14712598.2015.1009034","article-title":"Thymosin \u03b11 inserts N terminus into model membranes assuming a helical conformation","volume":"15","author":"Nepravishta","year":"2015","journal-title":"Expert Opin Biol Ther"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1080\/14712598.2018.1474198","article-title":"Deciphering cellular biological processes to clinical application: a new perspective for T\u03b11 treatment targeting multiple diseases","volume":"18","author":"Matteucci","year":"2018","journal-title":"Expert Opin Biol Ther"},{"key":"ref60","doi-asserted-by":"publisher","first-page":"13120","DOI":"10.1021\/bi7014822","article-title":"Effects of zinc binding on the structure and dynamics of the intrinsically disordered protein prothymosin alpha: evidence for metalation as an entropic switch","volume":"46","author":"Yi","year":"2007","journal-title":"Biochemistry"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1016\/j.tibs.2023.08.001","article-title":"Intrinsically disordered regions are poised to act as sensors of cellular chemistry","volume":"48","author":"Moses","year":"2023","journal-title":"Trends Biochem Sci"},{"key":"ref62","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1038\/nrm3920","article-title":"Intrinsically disordered proteins in cellular signalling and regulation","volume":"16","author":"Wright","year":"2015","journal-title":"Nat Rev Mol Cell Biol"},{"key":"ref63","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/nrm.2017.7","article-title":"Biomolecular condensates: organizers of cellular biochemistry","volume":"18","author":"Banani","year":"2017","journal-title":"Nat Rev Mol Cell Biol"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1196\/annals.1415.002","article-title":"Thymosin alpha1: an endogenous regulator of inflammation, immunity, and tolerance","volume":"1112","author":"Romani","year":"2007","journal-title":"Ann N Y Acad Sci"},{"key":"ref65","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1749-6632.2010.05465.x","article-title":"Thymosin alpha1: the regulator of regulators?","volume":"1194","author":"Pierluigi","year":"2010","journal-title":"Ann N Y Acad Sci"},{"key":"ref66","doi-asserted-by":"publisher","first-page":"109949","DOI":"10.1016\/j.intimp.2023.109949","article-title":"COVID-19 and beyond: reassessing the role of thymosin alpha1 in lung infections","volume":"117","author":"Bellet","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"ref67","doi-asserted-by":"publisher","first-page":"873","DOI":"10.3389\/fonc.2019.00873","article-title":"A reappraisal of Thymosin Alpha1 in Cancer therapy","volume":"9","author":"Costantini","year":"2019","journal-title":"Front Oncol"},{"key":"ref68","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1111\/j.1749-6632.2012.06707.x","article-title":"Thymosin alpha1 as a stimulatory agent of innate cell-mediated immune response","volume":"1270","author":"Serafino","year":"2012","journal-title":"Ann N Y Acad Sci"},{"key":"ref69","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/bs.vh.2016.04.003","article-title":"Immune modulation with Thymosin alpha 1 treatment","volume":"102","author":"King","year":"2016","journal-title":"Vitam Horm"},{"key":"ref70","doi-asserted-by":"publisher","first-page":"67","DOI":"10.5501\/wjv.v9.i5.67","article-title":"Thymosin alpha 1: a comprehensive review of the literature","volume":"9","author":"Dominari","year":"2020","journal-title":"World J Virol"},{"key":"ref71","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1016\/j.clinbiochem.2005.01.013","article-title":"Thymosin alpha 1 attenuates lipid peroxidation and improves fructose-induced steatohepatitis in rats","volume":"38","author":"Armutcu","year":"2005","journal-title":"Clin Biochem"},{"key":"ref72","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/S0165-5728(97)00189-6","article-title":"A role of the thymus and thymosin-alpha1 in brain NGF levels and NGF receptor expression","volume":"82","author":"Turrini","year":"1998","journal-title":"J Neuroimmunol"},{"key":"ref73","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/S0304-3940(03)00862-0","article-title":"Thymosin alpha-1 modulates excitatory synaptic transmission in cultured hippocampal neurons in rats","volume":"350","author":"Yang","year":"2003","journal-title":"Neurosci Lett"},{"key":"ref74","doi-asserted-by":"publisher","first-page":"5774","DOI":"10.1073\/pnas.83.16.5774","article-title":"Membrane lipid phase as catalyst for peptide-receptor interactions","volume":"83","author":"Sargent","year":"1986","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref75","first-page":"51","article-title":"Pharmacokinetics of thymosin alpha1 after subcutaneous injection of three different formulations in healthy volunteers","volume":"37","author":"Rost","year":"1999","journal-title":"Int J Clin Pharmacol Ther"},{"key":"ref76","first-page":"698","article-title":"Thymosin alpha1. SciClone pharmaceuticals","volume":"3","author":"Billich","year":"2002","journal-title":"Curr Opin Investig Drugs"},{"key":"ref77","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1111\/cei.12833","article-title":"Serum thymosin \u03b1 1 levels in patients with chronic inflammatory autoimmune diseases","volume":"186","author":"Pica","year":"2016","journal-title":"Clin Exp Immunol"},{"key":"ref78","first-page":"6","article-title":"Comprehensive review of the safety and efficacy of Thymosin alpha 1 in human clinical trials","volume":"30","author":"Dinetz","year":"2024","journal-title":"Altern Ther Health Med"},{"key":"ref79","doi-asserted-by":"publisher","first-page":"111103","DOI":"10.1016\/j.intimp.2023.111103","article-title":"Immune modulation via dendritic cells by the effect of Thymosin-alpha-1 on immune synapse in HCMV infection","volume":"125","author":"Espinar-Buitrago","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"ref80","doi-asserted-by":"publisher","first-page":"3539","DOI":"10.3390\/molecules28083539","article-title":"Thymosin alpha1 and its role in viral infectious diseases: the mechanism and clinical application","volume":"28","author":"Tao","year":"2023","journal-title":"Molecules"},{"key":"ref81","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1080\/14712598.2018.1451511","article-title":"Combination of entecavir with thymosin alpha-1 in HBV-related compensated cirrhosis: a prospective multicenter randomized open-label study","volume":"18","author":"Wu","year":"2018","journal-title":"Expert Opin Biol Ther"},{"key":"ref82","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1111\/jvh.12807","article-title":"Immunotherapy for hepatitis B in the direct acting antiviral era: reevaluating the thymosin \u03b11 efficacy trials in the light of a combination therapy approach","volume":"25","author":"Naylor","year":"2018","journal-title":"J Viral Hepat"},{"key":"ref83","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1111\/j.1749-6632.2010.05460.x","article-title":"Thymosin alpha 1 for treatment of hepatitis C virus: promise and proof","volume":"1194","author":"Sherman","year":"2010","journal-title":"Ann N Y Acad Sci"},{"key":"ref84","doi-asserted-by":"publisher","first-page":"141","DOI":"10.2217\/fmb-2016-0125","article-title":"Thymosin alpha 1 and HIV-1: recent advances and future perspectives","volume":"12","author":"Matteucci","year":"2017","journal-title":"Future Microbiol"},{"key":"ref85","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1186\/s12879-016-1823-5","article-title":"The efficacy of thymosin \u03b11 as immunomodulatory treatment for sepsis: a systematic review of randomized controlled trials","volume":"16","author":"Liu","year":"2016","journal-title":"BMC Infect Dis"},{"key":"ref86","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.ijid.2014.12.032","article-title":"Thymosin alpha1 based immunomodulatory therapy for sepsis: a systematic review and meta-analysis","volume":"33","author":"Li","year":"2015","journal-title":"Int J Infect Dis"},{"key":"ref87","doi-asserted-by":"publisher","first-page":"109584","DOI":"10.1016\/j.intimp.2022.109584","article-title":"Thymosin alpha1 use in adult COVID-19 patients: a systematic review and meta-analysis on clinical outcomes","volume":"114","author":"Shang","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"ref88","doi-asserted-by":"publisher","first-page":"109996","DOI":"10.1016\/j.intimp.2023.109996","article-title":"Novel evidence of Thymosin \u03b11 immunomodulatory properties in SARS-CoV-2 infection: effect on innate inflammatory response in a peripheral blood mononuclear cell-based in vitro model","volume":"117","author":"Ricci","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"ref89","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s12979-023-00351-x","article-title":"The use of alpha 1 thymosin as an immunomodulator of the response against SARS-Cov2","volume":"20","author":"Espinar-Buitrago","year":"2023","journal-title":"Immun Ageing"},{"key":"ref90","doi-asserted-by":"publisher","first-page":"109950","DOI":"10.1016\/j.intimp.2023.109950","article-title":"A pilot trial of Thymalfasin (Ta1) to prevent covid-19 infection and morbidities in renal dialysis patients: preliminary report","volume":"117","author":"Tuthill","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"ref91","doi-asserted-by":"publisher","first-page":"110055","DOI":"10.1016\/j.intimp.2023.110055","article-title":"Thymosin alpha 1 restores the immune homeostasis in lymphocytes during post-acute sequelae of SARS-CoV-2 infection","volume":"118","author":"Minutolo","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"ref92","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1093\/infdis\/jiac362","article-title":"A pilot trial of Thymalfasin (Thymosin-alpha-1) to treat hospitalized patients with hypoxemia and Lymphocytopenia due to coronavirus disease 2019 infection","volume":"227","author":"Shehadeh","year":"2023","journal-title":"J Infect Dis"},{"key":"ref93","doi-asserted-by":"publisher","first-page":"3317","DOI":"10.1007\/s10787-023-01354-2","article-title":"The efficacy of thymosin alpha-1 therapy in moderate to critical COVID-19 patients: a systematic review, meta-analysis, and meta-regression","volume":"31","author":"Soeroto","year":"2023","journal-title":"Inflammopharmacology"},{"key":"ref94","doi-asserted-by":"publisher","first-page":"110983","DOI":"10.1016\/j.intimp.2023.110983","article-title":"Thymosin alpha1 modulated the immune landscape of COVID-19 patients revealed by single-cell RNA and TCR sequencing","volume":"124","author":"Bai","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"ref95","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s41479-023-00116-6","article-title":"Thymalfasin therapy accelerates COVID-19 pneumonia rehabilitation through anti-inflammatory mechanisms","volume":"15","author":"Wang","year":"2023","journal-title":"Pneumonia (Nathan)"},{"key":"ref96","doi-asserted-by":"publisher","first-page":"664776","DOI":"10.3389\/fmed.2021.664776","article-title":"Efficacy evaluation of Thymosin alpha 1 in non-severe patients with COVID-19: a retrospective cohort study based on propensity score matching","volume":"8","author":"Huang","year":"2021","journal-title":"Front Med (Lausanne)"},{"key":"ref97","doi-asserted-by":"publisher","first-page":"913","DOI":"10.5005\/jp-journals-10071-24298","article-title":"A double-blind multicenter two-arm randomized placebo-controlled phase-III clinical study to evaluate the effectiveness and safety of Thymosin alpha1 as an add-on treatment to existing standard of care treatment in moderate-to-severe COVID-19 patients","volume":"26","author":"Shetty","year":"2022","journal-title":"Ind J Crit Care Med"},{"key":"ref98","doi-asserted-by":"publisher","first-page":"107143","DOI":"10.1016\/j.intimp.2020.107143","article-title":"The effect of thymosin alpha1 on mortality of critical COVID-19 patients: a multicenter retrospective study","volume":"90","author":"Sun","year":"2021","journal-title":"Int Immunopharmacol"},{"key":"ref99","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.ajem.2021.04.043","article-title":"Thymosin a1 use is not associated with reduced COVID-19 mortality","volume":"53","author":"Liu","year":"2022","journal-title":"Am J Emerg Med"},{"key":"ref100","doi-asserted-by":"publisher","first-page":"568789","DOI":"10.3389\/fimmu.2021.568789","article-title":"Thymosin Alpha-1 has no beneficial effect on restoring CD4+ and CD8+ T lymphocyte counts in COVID-19 patients","volume":"12","author":"Wang","year":"2021","journal-title":"Front Immunol"},{"key":"ref101","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1080\/03007995.2020.1853508","article-title":"Risk factors of mortality and contribution of treatment in patients infected with COVID-19: a retrospective propensity score matched study","volume":"37","author":"Wang","year":"2021","journal-title":"Curr Med Res Opin"},{"key":"ref102","doi-asserted-by":"publisher","first-page":"673693","DOI":"10.3389\/fimmu.2021.673693","article-title":"Efficacy of Thymosin alpha 1 in the treatment of COVID-19: a multicenter cohort study","volume":"12","author":"Liu","year":"2021","journal-title":"Front Immunol"},{"key":"ref103","doi-asserted-by":"publisher","first-page":"107022","DOI":"10.1016\/j.intimp.2020.107022","article-title":"Gender-associated difference following COVID-19 virus infection: implications for thymosin alpha-1 therapy","volume":"90","author":"Li","year":"2021","journal-title":"Int Immunopharmacol"},{"key":"ref104","doi-asserted-by":"publisher","DOI":"10.15761\/MRI.1000157","article-title":"Assessment the immune function of aged patients before and after immunotherapy in severe sepsis","volume":"3","author":"Cong","year":"2019","journal-title":"Med Res Innovat"},{"key":"ref105","doi-asserted-by":"publisher","first-page":"S31","DOI":"10.1517\/14712598.2015.1017466","article-title":"Historical review on thymosin \u03b11 in oncology: preclinical and clinical experiences","volume":"15","author":"Garaci","year":"2015","journal-title":"Expert Opin Biol Ther"},{"key":"ref106","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1097\/00002371-199301000-00002","article-title":"Antitumor effect of Thymosin \u03b11\/Interleukin-2 or Thymosin \u03b11\/interferon \u03b1,\u03b2 following cyclophosphamide in mice injected with highly metastatic friend Erythroleukemia cells","volume":"13","author":"Garaci","year":"1993","journal-title":"J Immunother Emphasis Tumor Immunol"},{"key":"ref107","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1002\/ijc.2910500327","article-title":"Combination therapy with thymosin alpha 1 potentiates the anti-tumor activity of interleukin-2 with cyclophosphamide in the treatment of the Lewis lung carcinoma in mice","volume":"50","author":"Mastino","year":"1992","journal-title":"Int J Cancer"},{"key":"ref108","doi-asserted-by":"publisher","first-page":"2700","DOI":"10.1097\/CM9.0000000000001819","article-title":"Impact of thymosin \u03b11 as an immunomodulatory therapy on long-term survival of non-small cell lung cancer patients after R0 resection: a propensity score-matched analysis","volume":"134","author":"Guo","year":"2021","journal-title":"Chin Med J"},{"key":"ref109","doi-asserted-by":"publisher","first-page":"1780","DOI":"10.1200\/JCO.2009.25.5208","article-title":"Large randomized study of thymosin alpha 1, interferon alfa, or both in combination with dacarbazine in patients with metastatic melanoma","volume":"28","author":"Maio","year":"2010","journal-title":"J Clin Oncol"},{"key":"ref110","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1111\/j.1749-6632.2012.06697.x","article-title":"Thymosin \u03b11 and cancer: action on immune effector and tumor target cells","volume":"1269","author":"Garaci","year":"2012","journal-title":"Ann N Y Acad Sci"},{"key":"ref111","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1016\/j.ijrobp.2022.07.009","article-title":"Efficacy of Thymosin \u03b11 in Management of Radiation Pneumonitis in patients with locally advanced non-small cell lung Cancer treated with concurrent Chemoradiotherapy: a phase 2 clinical trial (GASTO-1043)","volume":"114","author":"Liu","year":"2022","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"ref112","doi-asserted-by":"publisher","first-page":"659065","DOI":"10.3389\/fonc.2021.659065","article-title":"The efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitor combined with Thymosin in advanced non-small cell lung Cancer patients harboring active epidermal growth factor receptor mutations","volume":"11","author":"Feng","year":"2021","journal-title":"Front Oncol"},{"key":"ref113","doi-asserted-by":"publisher","first-page":"1991","DOI":"10.1158\/0008-5472.CAN-21-4260","article-title":"Thymosin \u03b1-1 reverses M2 polarization of tumor-associated macrophages during Efferocytosis","volume":"82","author":"Wei","year":"2022","journal-title":"Cancer Res"},{"key":"ref114","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1080\/14712598.2018.1494717","article-title":"Long-term follow up of metastatic melanoma patients treated with Thymosin alpha-1: investigating immune checkpoints synergy","volume":"18","author":"Danielli","year":"2018","journal-title":"Expert Opin Biol Ther"},{"key":"ref115","doi-asserted-by":"publisher","first-page":"e202000662","DOI":"10.26508\/lsa.202000662","article-title":"Thymosin \u03b11 protects from CTLA-4 intestinal immunopathology","volume":"3","author":"Renga","year":"2020","journal-title":"Life Sci Alliance"},{"key":"ref116","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.msard.2018.09.035","article-title":"Thymosins in multiple sclerosis and its experimental models: moving from basic to clinical application","volume":"27","author":"Severa","year":"2019","journal-title":"Mult Scler Relat Disord"},{"key":"ref117","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1080\/14712598.2018.1474197","article-title":"Serum thymosin alpha 1 levels in normal and pathological conditions","volume":"18","author":"Pica","year":"2018","journal-title":"Expert Opin Biol Ther"},{"key":"ref118","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1111\/j.1749-6632.2010.05482.x","article-title":"Thymosin alpha 1: past clinical experience and future promise","volume":"1194","author":"Tuthill","year":"2010","journal-title":"Ann N Y Acad Sci"},{"key":"ref119","doi-asserted-by":"publisher","first-page":"110168","DOI":"10.1016\/j.intimp.2023.110168","article-title":"Reduced numbers of na\u00efve CD4 + T cells and an altered CD4\/CD8 balance in depressed common variable immune deficiency (CVID) patients. Is thymosin-\u03b11 a possible treatment?","volume":"119","author":"Manusama","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"ref120","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1080\/13543776.2023.2298833","article-title":"Therapeutic applications of thymosin peptides: a patent landscape 2018-present","volume":"33","author":"Quagliata","year":"2023","journal-title":"Expert Opin Ther Pat"},{"key":"ref121","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.drudis.2014.10.003","article-title":"Peptide therapeutics: current status and future directions","volume":"20","author":"Fosgerau","year":"2015","journal-title":"Drug Discov Today"},{"key":"ref122","doi-asserted-by":"publisher","first-page":"124","DOI":"10.3390\/ijms22010124","article-title":"PASylated Thymosin \u03b11: a long-acting imamunostimulatory peptide for applications in oncology and virology","volume":"22","author":"Binder","year":"2020","journal-title":"Int J Mol Sci"},{"key":"ref123","doi-asserted-by":"publisher","first-page":"12351","DOI":"10.1038\/s41598-018-30956-y","article-title":"Thymosin Alpha1-fc modulates the immune system and Down-regulates the progression of melanoma and breast Cancer with a prolonged half-life","volume":"8","author":"Wang","year":"2018","journal-title":"Sci Rep"},{"key":"ref124","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/1475-2859-10-26","article-title":"Production of N\u03b1-acetylated thymosin \u03b11 in Escherichia coli","volume":"10","author":"Ren","year":"2011","journal-title":"Microb Cell Factories"},{"key":"ref125","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.intimp.2012.12.031","article-title":"Thymosin alpha-1-transformed Bifidobacterium promotes T cell proliferation and maturation in mice by oral administration","volume":"15","author":"Shao","year":"2013","journal-title":"Int Immunopharmacol"},{"key":"ref126","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.tips.2020.01.003","article-title":"Context-dependent pharmacological effects of metformin on the immune system","volume":"41","author":"Marcucci","year":"2020","journal-title":"Trends Pharmacol Sci"},{"key":"ref127","doi-asserted-by":"publisher","first-page":"1527","DOI":"10.1016\/j.cell.2024.01.028","article-title":"Direct interrogation of context-dependent GPCR activity with a universal biosensor platform","volume":"187","author":"Janicot","year":"2024","journal-title":"Cell"},{"key":"ref128","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1038\/d41586-024-00327-x","article-title":"It's time to admit that genes are not the blueprint for life","volume":"626","author":"Noble","year":"2024","journal-title":"Nature"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2024.1388959\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T19:26:48Z","timestamp":1718134008000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2024.1388959\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,6]]},"references-count":128,"alternative-id":["10.3389\/fmed.2024.1388959"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2024.1388959","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,6]]},"article-number":"1388959"}}