{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T23:25:19Z","timestamp":1789601119956,"version":"build-2803163510"},"reference-count":40,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,8,27]],"date-time":"2022-08-27T00:00:00Z","timestamp":1661558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Gravitas Therapeutics"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoF"],"abstract":"<jats:p>GR-2397 (previously VL-2397, ASP2397) is a first-in-class antifungal agent for the treatment of invasive aspergillosis. This siderophore-like molecule resembles ferrichrome; however, it is differentiated by three amino acid changes and an aluminum rather than iron chelate. GR-2397 is transported into fungal cells via the Sit1 transporter, which is not found in humans, leading to fungal specificity. Although the precise mechanism of action is currently unknown, GR-2397 is active against Aspergillus spp. including azole-resistant strains, Fusarium solani, and Candida glabrata in addition to other organisms. Efficacy has been demonstrated in several animal models of invasive aspergillosis, including a 24 h delayed-treatment model where rapid fungicidal activity was observed. Phase 1 single- and multiple-ascending intravenous dose studies showed that GR-2397 was safe and well-tolerated in humans. No signs of GR-2397 accumulation were observed following IV infusions of 300, 600, and 1200 mg every 24 h (q24h) for 7 days. The favorable safety, tolerability and drug\u2013drug interaction profile, along with good tissue distribution, support further development of GR-2397 as a new treatment option for patients with invasive aspergillosis. This systematic review summarizes the published findings of GR-2397.<\/jats:p>","DOI":"10.3390\/jof8090909","type":"journal-article","created":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T03:34:56Z","timestamp":1661744096000},"page":"909","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["GR-2397: Review of the Novel Siderophore-like Antifungal Agent for the Treatment of Invasive Aspergillosis"],"prefix":"10.3390","volume":"8","author":[{"given":"Karen Joy","family":"Shaw","sequence":"first","affiliation":[{"name":"Hearts Consulting Group, LLC, Poway, CA 92064, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bongomin, F., Gago, S., Oladele, R.O., and Denning, D.W. (2017). Global and Multi-National Prevalence of Fungal Diseases-Estimate Precision. J. Fungi, 3.","DOI":"10.3390\/jof3040057"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1086\/652768","article-title":"Factors associated with mortality in transplant patients with invasive aspergillosis","volume":"50","author":"Baddley","year":"2010","journal-title":"Clin. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"165rv113","DOI":"10.1126\/scitranslmed.3004404","article-title":"Hidden killers: Human fungal infections","volume":"4","author":"Brown","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1086\/651263","article-title":"Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001\u20132006: Overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database","volume":"50","author":"Kontoyiannis","year":"2010","journal-title":"Clin. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1086\/323900","article-title":"The impact of culture isolation of Aspergillus species: A hospital-based survey of aspergillosis","volume":"33","author":"Perfect","year":"2001","journal-title":"Clin. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Jenks, J.D., and Hoenigl, M. (2018). Treatment of Aspergillosis. J. Fungi, 4.","DOI":"10.3390\/jof4030098"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1093\/mmy\/myw060","article-title":"The anti-Aspergillus drug pipeline: Is the glass half full or empty?","volume":"55","author":"Osherov","year":"2017","journal-title":"Med. Mycol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1055\/s-0035-1562894","article-title":"Emergence of Azole Resistance in Aspergillus","volume":"36","author":"Wiederhold","year":"2015","journal-title":"Semin. Respir. Crit. Care Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/nrd.2017.46","article-title":"The antifungal pipeline: A reality check","volume":"16","author":"Perfect","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e00969-19","DOI":"10.1128\/AAC.00969-19","article-title":"First-in-Human Phase 1 Study To Assess Safety, Tolerability, and Pharmacokinetics of a Novel Antifungal Drug, VL-2397, in Healthy Adults","volume":"63","author":"Mammen","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_11","unstructured":"Nakamura, I., Yoshikawa, K., Masaki, T., Kanasaki, R., and Shahab, N. (2012). Microorganism Producing Cyclic Compound. (US8241872B2), U.S. Patent."},{"key":"ref_12","unstructured":"Nakamura, I., Ohsumi, K., Yoshikawa, K., Kanasaki, R., Masaki, T., Takase, S., Hashimoto, M., Fuije, A., and Nakait, T. (2014). ASP2397: A Novel Natural Product with Potent Fungicidal Activity against Aspergillus spp. (1)\u2014A New Mode of Action and In Vitro Activity, ICAAC. Abstract #F-1590."},{"key":"ref_13","unstructured":"Nakamura, I., Nakai, T., Matsumoto, S., Takeda, S., Akamatsu, S., Uchida, S., Koide, Y., Mitori, H., Noto, T., and Maki, K. (2014). ASP2397: A Novel Natural Product with Potent Fungicidal Activity against Aspergillus spp. (2)\u2014In Vivo Activity against A. fumigatus, ICAAC. Abstract #F-1591."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/ja.2016.107","article-title":"ASP2397: A novel antifungal agent produced by Acremonium persicinum MF-347833","volume":"70","author":"Nakamura","year":"2017","journal-title":"J. Antibiot."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/ja.2016.106","article-title":"Discovery of a new antifungal agent ASP2397 using a silkworm model of Aspergillus fumigatus infection","volume":"70","author":"Nakamura","year":"2017","journal-title":"J. Antibiot."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"373","DOI":"10.3389\/fmicb.2017.00373","article-title":"Advantages of the Silkworm As an Animal Model for Developing Novel Antimicrobial Agents","volume":"8","author":"Panthee","year":"2017","journal-title":"Front. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4224","DOI":"10.1021\/ja00532a039","article-title":"Crystal structure of ferrichrome and a comparison with the structure of ferrichrome A","volume":"102","author":"Baker","year":"1980","journal-title":"J. Am. Chem. Soc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2594","DOI":"10.1021\/acs.jnatprod.9b00545","article-title":"Natural Hydroxamate-Containing Siderophore Acremonpeptides A-D and an Aluminum Complex of Acremonpeptide D from the Marine-Derived Acremonium persicinum SCSIO 115","volume":"82","author":"Luo","year":"2019","journal-title":"J. Nat. Prod."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Li, Y., and Li, Z. (2021). Cyclopeptide Derivatives from the Sponge-Derived Fungus Acremonium persicinum F10. Mar. Drugs, 19.","DOI":"10.3390\/md19100537"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1021\/acschembio.1c00867","article-title":"Differential Biosynthesis and Roles of Two Ferrichrome-Type Siderophores, ASP2397\/AS2488053 and Ferricrocin, in Acremonium persicinum","volume":"17","author":"Asai","year":"2022","journal-title":"ACS Chem. Biol."},{"key":"ref_21","unstructured":"CLSI (2017). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi, Clinical and Laboratory Standards Institute. [3rd. ed.]. CLSI standard M38."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e00807-19","DOI":"10.1128\/AAC.00807-19","article-title":"The Siderophore Transporter Sit1 Determines Susceptibility to the Antifungal VL-2397","volume":"63","author":"Dietl","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.bbamcr.2006.05.008","article-title":"Iron uptake in fungi: A system for every source","volume":"1763","author":"Philpott","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Aguiar, M., Orasch, T., Misslinger, M., Dietl, A.M., Gsaller, F., and Hass, H. (2021). The Siderophore Transporters Sit1 and Sit2 Are Essential for Utilization of Ferrichrome-, Ferrioxamine- and Coprogen-Type Siderophores in Aspergillus fumigatus. J. Fungi, 7.","DOI":"10.3390\/jof7090768"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e02689-18","DOI":"10.1128\/AAC.02689-18","article-title":"ASP2397 Is a Novel Natural Compound That Exhibits Rapid and Potent Fungicidal Activity against Aspergillus Species through a Specific Transporter","volume":"63","author":"Nakamura","year":"2019","journal-title":"Antimicrob. Agents Chemother"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5664","DOI":"10.1073\/pnas.1030323100","article-title":"The mechanism of ferrichrome transport through Arn1p and its metabolism in Saccharomyces cerevisiae","volume":"100","author":"Moore","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/S0092-8674(00)80358-X","article-title":"Nonfilamentous C. albicans mutants are avirulent","volume":"90","author":"Lo","year":"1997","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1042\/BCJ20160066","article-title":"Identification of ferrichrome- and ferrioxamine B-mediated iron uptake by Aspergillus fumigatus","volume":"473","author":"Park","year":"2016","journal-title":"Biochem. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5246","DOI":"10.1128\/IAI.70.9.5246-5255.2002","article-title":"The siderophore iron transporter of Candida albicans (Sit1p\/Arn1p) mediates uptake of ferrichrome-type siderophores and is required for epithelial invasion","volume":"70","author":"Heymann","year":"2002","journal-title":"Infect. Immun."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Nevitt, T., and Thiele, D.J. (2011). Host iron withholding demands siderophore utilization for Candida glabrata to survive macrophage killing. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1001322"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1111\/j.1348-0421.2007.tb04000.x","article-title":"Direct comparison of the pharmacodynamics of four antifungal drugs in a mouse model of disseminated candidiasis using microbiological assays of serum drug concentrations","volume":"51","author":"Maki","year":"2007","journal-title":"Microbiol. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1128\/AAC.02336-15","article-title":"In Vitro Activity of ASP2397 against Aspergillus Isolates with or without Acquired Azole Resistance Mechanisms","volume":"60","author":"Arendrup","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_33","unstructured":"Arendrup, M.C., Hope, W.W., and Howard, S.J. (2014). EUCAST Definitive Document E. Def 9.2 Method for the Determination of Broth Dilution Minimum Inhibitory Concentrations of Antifungal Agents for Conidia Forming Moulds. Available online: https:\/\/www.aspergillus.org.uk\/wp-content\/uploads\/2016\/03\/EUCAST_E_Def_9_3_Mould_testing_definitive_0.pdf."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e01157-17","DOI":"10.1128\/mBio.01157-17","article-title":"Pharmacodynamics of the Orotomides against Aspergillus fumigatus: New Opportunities for Treatment of Multidrug-Resistant Fungal Disease","volume":"8","author":"Hope","year":"2017","journal-title":"mBio"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1093\/infdis\/jir023","article-title":"Pharmacokinetics and pharmacodynamics of posaconazole for invasive pulmonary aspergillosis: Clinical implications for antifungal therapy","volume":"203","author":"Howard","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_36","unstructured":"Wiederhold, N.P., Najvar, L.K., Jaramillo, R., Olivo, M., Catano, G., Sullivan, S.M., Hopkins, A.M., Smith, L.R., and Patterson, T.F. (2017). The Novel Antifungal VL-2397 Demonstrates Efficacy in an In Vivo Model of Invasive Candidiasis Caused by Wild-Type and Multi-Drug Resistant Candida glabrata, ASM Microbe. Poster #1222."},{"key":"ref_37","unstructured":"Nakamura, I., Ohbuchi, M., Akabane, T., Akamatsu, S., Matsumoto, S., Takeda, S., Hodges, M., Smith, L.R., and Sullivan, S.M. (2015). Pharmacokinetic and Pharmacodynamic Characterization of ASP2397 (VL-2397), a Novel Potent Antifungal Agent with Acitivity Against Pulmonary Aspergillosis, ICAAC. Abstract #F-746."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Rubino, C.M., Smith, L.R., Mammen, M.P., Hopkins, A.M., Lakota, E.A., and Sullivan, S.M. (2017). Pharmacokinetic-Pharmacodynamic Target Attainment Analysis to Support VL-2397 Dose Selection for a Phase 2 Trial in Patients with Invasive Aspergillosis, IDWeek. Abstract #1515.","DOI":"10.1093\/ofid\/ofx163.1211"},{"key":"ref_39","unstructured":"Nakamura, I., Ohbuchi, M., Matsumoto, S., Smith, L.R., and Sullivan, S.M. (2017). Characterization of Potential Drug Interactions and Off-Target Activities of VL-2397, A Novel Antifungal Agent against Invasive Aspergillosis, ASM Microbe. Abst #235."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e00163-19","DOI":"10.1128\/AAC.00163-19","article-title":"Population Pharmacokinetic Modeling of VL-2397, a Novel Systemic Antifungal Agent: Analysis of a Single- and Multiple-Ascending-Dose Study in Healthy Subjects","volume":"63","author":"Kovanda","year":"2019","journal-title":"Antimicrob. Agents Chemother."}],"container-title":["Journal of Fungi"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2309-608X\/8\/9\/909\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:16:34Z","timestamp":1760141794000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2309-608X\/8\/9\/909"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,27]]},"references-count":40,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["jof8090909"],"URL":"https:\/\/doi.org\/10.3390\/jof8090909","relation":{},"ISSN":["2309-608X"],"issn-type":[{"value":"2309-608X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,27]]}}}