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1
Li, Jiaqi. "Advances and applications of prodrug strategies in drug design." Journal of Food Science, Nutrition and Health 3, no. 1 (November 18, 2024): 12–22. https://doi.org/10.54254/3029-0821/3/2024023.
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Of all the drugs launched on the market over the past decade, a substantial number of approved prodrugs have been significant, underscoring the importance of this prodrug to drug design. It is reported that 10% of all marketed drugs globally can be classified as prodrugs. The core goal of the prodrug strategy is to improve the undesirable properties of the drug molecule, including but not limited to insufficient solubility, low selectivity, poor chemical stability, poor taste, strong local irritation, significant pain, and possible systemic toxicity during metabolism in vivo. This review article includes the discussion of the phosphate prodrugs, ketone prodrugs, ester prodrugs, amide prodrugs, pH-responsive prodrugs, enzyme-activated prodrugs, carbamate prodrugs, liposomal prodrugs, and pleiotropic prodrugs. The latest research on prodrugs in the field of cancer, nano and antibacterial in recent years are also discussed. Through the research and application of the above chemical modification methods and the clinical application of prodrug technology in the fields of cancer treatment, nanotechnology, antimicrobial drugs, etc., researchers can design safer and more effective treatments to meet clinical needs and optimize the treatment experience of patients. At the same time, these studies not only confirm the importance of prodrug design in drug development, but also provide new ideas and methods for future drug design.
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Toublet, François-Xavier, Cédric Lecoutey, Julien Lalut, Bérénice Hatat, Audrey Davis, Marc Since, Sophie Corvaisier, et al. "Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease." Molecules 24, no. 15 (July 31, 2019): 2786. http://dx.doi.org/10.3390/molecules24152786.
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Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly acetylcholinesterase inhibitors (AChEI), are considered clinically insufficient and are responsible for deleterious side effects. AChE is, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But AChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central AChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects. We aim in this article to pave the road of this new avenue with an in vitro and in vivo study of pleiotropic prodrugs targeting both the 5-HT4 receptor and AChE, in order to display a neuroprotective activity associated with a sustained restoration of the cholinergic neurotransmission and without the usual peripheral side effects associated with classic AChEI. This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits.
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Chirumbolo, Salvatore, Geir Bjørklund, Roman Lysiuk, Antonio Vella, Larysa Lenchyk, and Taras Upyr. "Targeting Cancer with Phytochemicals via Their Fine Tuning of the Cell Survival Signaling Pathways." International Journal of Molecular Sciences 19, no. 11 (November 12, 2018): 3568. http://dx.doi.org/10.3390/ijms19113568.
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The role of phytochemicals as potential prodrugs or therapeutic substances against tumors has come in the spotlight in the very recent years, thanks to the huge mass of encouraging and promising results of the in vitro activity of many phenolic compounds from plant raw extracts against many cancer cell lines. Little but important evidence can be retrieved from the clinical and nutritional scientific literature, where flavonoids are investigated as major pro-apoptotic and anti-metastatic compounds. However, the actual role of these compounds in cancer is still far to be fully elucidated. Many of these phytochemicals act in a pleiotropic and poorly specific manner, but, more importantly, they are able to tune the reactive oxygen species (ROS) signaling to activate a survival or a pro-autophagic and pro-apoptosis mechanism, depending on the oxidative stress-responsive endowment of the targeted cell. This review will try to focus on this issue.
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Campos-Salinas, Jenny, Margarita Barriga, and Mario Delgado. "Therapeutic Effect of a Latent Form of Cortistatin in Experimental Inflammatory and Fibrotic Disorders." Pharmaceutics 14, no. 12 (December 13, 2022): 2785. http://dx.doi.org/10.3390/pharmaceutics14122785.
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Cortistatin is a cyclic neuropeptide that recently emerged as an attractive therapeutic factor for treating inflammatory, autoimmune, fibrotic, and pain disorders. Despite of its efficiency and apparent safety in experimental preclinical models, its short half-life in body fluids and its potential pleiotropic effects, due to its promiscuity for several receptors expressed in various cells and tissues, represent two major drawbacks for the clinical translation of cortistatin-based therapies. Therefore, the design of new strategies focused on increasing the stability, bioavailability, and target specificity of cortistatin are lately demanded by the industry. Here, we generated by molecular engineering a new cortistatin-based prodrug formulation that includes, beside the bioactive cortistatin, a molecular-shield provided by the latency-associated protein of the transforming growth factor-β1 and a cleavage site specifically recognized by metalloproteinases, which are abundant in inflammatory/fibrotic foci. Using different models of sepsis, inflammatory bowel disease, scleroderma, and pulmonary fibrosis, we demonstrated that this latent form of cortistatin was a highly effective protection against these severe disorders. Noteworthy, from a therapeutic point of view, is that latent cortistatin seems to require significantly lower doses and fewer administrations than naive cortistatin to reach the same efficacy. Finally, the metalloproteinase-cleavage site was essential for the latent molecule to exert its therapeutic action. In summary, latent cortistatin emerges as a promising innovative therapeutic tool for treating chronic diseases of different etiologies with difficult clinical solutions and as a starting point for a rational development of prodrugs based on the use of bioactive peptides.
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Toublet, François-Xavier, Julien Lalut, Bérénice Hatat, Cédric Lecoutey, Audrey Davis, Marc Since, Sophie Corvaisier, et al. "Pleiotropic prodrugs: Design of a dual butyrylcholinesterase inhibitor and 5-HT6 receptor antagonist with therapeutic interest in Alzheimer’s disease." European Journal of Medicinal Chemistry 210 (January 2021): 113059. http://dx.doi.org/10.1016/j.ejmech.2020.113059.
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Leitsch, David. "A review on metronidazole: an old warhorse in antimicrobial chemotherapy." Parasitology 146, no. 9 (November 23, 2017): 1167–78. http://dx.doi.org/10.1017/s0031182017002025.
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AbstractThe 5-nitroimidazole drug metronidazole has remained the drug of choice in the treatment of anaerobic infections, parasitic as well as bacterial, ever since its development in 1959. In contrast to most other antimicrobials, it has a pleiotropic mode of action and reacts with a large number of molecules. Importantly, metronidazole, which is strictly speaking a prodrug, needs to be reduced at its nitro group in order to become toxic. Reduction of metronidazole, however, only takes place under very low concentrations of oxygen, explaining why metronidazole is exclusively toxic to microaerophilic and anaerobic microorganisms. In general, resistance rates amongst the pathogens treated with metronidazole have remained low until the present day. Nevertheless, metronidazole resistance does occur, and for the treatment of some pathogens, especiallyHelicobacter pylori, metronidazole has become almost useless in some parts of the world. This review will give an account on the current status of research on metronidazole's mode of action, metronidazole resistance in eukaryotes and prokaryotes, and on other 5-nitroimidazoles in use.
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Bettendorff, Lucien. "Synthetic Thioesters of Thiamine: Promising Tools for Slowing Progression of Neurodegenerative Diseases." International Journal of Molecular Sciences 24, no. 14 (July 10, 2023): 11296. http://dx.doi.org/10.3390/ijms241411296.
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Thiamine (vitamin B1) is essential for the brain. This is attributed to the coenzyme role of thiamine diphosphate (ThDP) in glucose and energy metabolism. The synthetic thiamine prodrug, the thioester benfotiamine (BFT), has been extensively studied and has beneficial effects both in rodent models of neurodegeneration and in human clinical studies. BFT has no known adverse effects and improves cognitive outcomes in patients with mild Alzheimer’s disease. In cell culture and animal models, BFT has antioxidant and anti-inflammatory properties that seem to be mediated by a mechanism independent of the coenzyme function of ThDP. Recent in vitro studies show that another thiamine thioester, O,S-dibenzoylthiamine (DBT), is even more efficient than BFT, especially with respect to its anti-inflammatory potency, and is effective at lower concentrations. Thiamine thioesters have pleiotropic properties linked to an increase in circulating thiamine concentrations and possibly in hitherto unidentified open thiazole ring derivatives. The identification of the active neuroprotective metabolites and the clarification of their mechanism of action open extremely promising perspectives in the field of neurodegenerative, neurodevelopmental, and psychiatric conditions. The present review aims to summarize existing data on the neuroprotective effects of thiamine thioesters and give a comprehensive account.
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Nirschl, Christopher J., Pam Alderhold, Heather R. Brodkin, Connor J. Dwyer, Daniel J. Hicklin, Nesreen Ismail, Andres Salmeron, et al. "Abstract 2055: WTX-330 is a conditionally activated IL-12 prodrug that fundamentally reprograms tumor infiltrating CD8+ T cells and drives tumor regression." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2055. http://dx.doi.org/10.1158/1538-7445.am2022-2055.
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Abstract Immune checkpoint inhibition (ICI) has established immunotherapy as the first line of treatment in a subset of cancers. However, there are still many patients and cancer types where ICI is not effective, representing a significant unmet clinical need for novel immunotherapies to expand the clinical options for patients. Interleukin 12 (IL-12) is a pleiotropic cytokine that drives naïve T cells towards a TH1 phenotype, activates NK cells and cytotoxic T cells, and strongly induces the expression of IFNγ by multiple cell types, making it an attractive pro-inflammatory cytokine for cancer immunotherapy. However, despite its demonstrated clinical benefits, poor pharmacokinetic properties and dose-limiting toxicities after systemic administration have greatly limited the use of IL-12 in the clinic. WTX-330 is a novel IL-12 pro-drug that is designed to harness the dysregulated protease activity of tumors to selectively deliver fully active IL-12 to the tumor microenvironment (TME). WTX-330 consists of wild-type IL-12 tethered to a high affinity antibody blockade domain and a half-life extension (HLE) domain via tumor protease-sensitive linkers. Following systemic administration, WTX-330 circulates as an inactive prodrug that is unable to bind to IL-12 receptors in normal tissues. When WTX-330 enters the tumor however, proteases found in the TME cleave the protease-sensitive linkers, releasing fully active IL-12 selectively in the tumor. WTX-330 is highly efficacious in murine syngeneic tumor models, leading to complete, CD8+ T cell dependent tumor regressions when MC38 tumor bearing mice were treated with a murine surrogate of WTX-330. Importantly, while murine WTX-330 was well tolerated by the mice, equimolar amounts of wild-type IL-12 was not, highlighting the tumor selective activity of the INDUKINE™ protein. Murine WTX-330 treatment of either MC38 or EMT6 tumor bearing mice increased the frequency of tumor infiltrating polyfunctional CD8+ T cells and activated tumor infiltrating NK cells in both models. In the EMT6 model, Geospatial NanoString analysis revealed significantly more tumor penetration by CD8+ T cells following murine WTX-330 treatment at multiple timepoints and demonstrated that systemic dosing with the IL-12 INDUKINE™ molecule resulted in IL-12 signaling by the tumor infiltrating CD8+ T cells. Furthermore, murine WTX-330 treatment fundamentally reprogrammed the metabolic program of tumor infiltrating CD8+ T cells, increasing both glycolysis and mitochondrial biogenesis, while also increasing TCR signaling and degranulation. Finally, ex vivo incubation of WTX-330 with various primary human tumors led to the release of active IL-12, while WTX-330 was stable in human serum and healthy human primary cells from various tissues. Together, these data support continued development of this innovative IL-12 therapy into clinical testing. Citation Format: Christopher J. Nirschl, Pam Alderhold, Heather R. Brodkin, Connor J. Dwyer, Daniel J. Hicklin, Nesreen Ismail, Andres Salmeron, Cynthia Seidel-Dugan, Philipp Steiner, Zoe Steuert, Jenna Sullivan, William M. Winston. WTX-330 is a conditionally activated IL-12 prodrug that fundamentally reprograms tumor infiltrating CD8+ T cells and drives tumor regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2055.
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Su, Qingtai, Stephen Gutowski, Austin Burcham, Bhargavi Allu, Zirong Chen, Fiona Stavros, Ruolan Han, Jason B. Miller, and Tian Zhao. "Abstract LB438: Preclinical characterization of ONM-412, an ultra-pH sensitive nanoparticle encapsulated IL-12 fusion protein." Cancer Research 84, no. 7_Supplement (April 5, 2024): LB438. http://dx.doi.org/10.1158/1538-7445.am2024-lb438.
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Abstract Background: Interleukin-12 is a potent pleiotropic cytokine, but its clinical translation has been hindered by toxicities. To deliver IL-12 to tumors with high spatial and temporal precision while minimizing off-tumor effects, we have developed an ultra-pH sensitive nanoparticle platform - ON-BOARD - that shields payloads from systemic exposure and targets solid tumors by responding to tumor acidity. Herein, we report the preclinical efficacy and safety characterization of ONM-412, an ON-BOARD nanoparticle encapsulated IL-12Fc fusion protein, and muONM-412, an encapsulated murine IL-12Fc. Methods: Properties and stability profiles of ONM-412 were characterized. pH-specific bioactivity was determined in cell-based reporter and IFNγ induction assays while the activation of ONM-412 was compared to a protease-cleavable IL-12 prodrug. Efficacy and tolerability of muONM-412 were studied in vivo after intravenous injection in mice. Pharmacodynamic response was evaluated by measuring cytokine levels in plasma and tissue, and the changes in tumor immune microenvironment were characterized. Toxicity was measured by body weight loss, systemic cytokine levels and clinical chemistry. Anti-tumor efficacy of muONM-412 was evaluated in MC38 tumor-bearing mice. The safety and tolerability of ONM-412 is also undergoing evaluation in a toxicology study with cynomolgus monkeys. Body weight, hematology, clinical chemistry and urine analysis were performed. Results: ONM-412 showed high encapsulation efficiency (>85%) in uniformly distributed particles (Dh<50nm) with 6-month on-going shelf-life stability. pH-specific release was confirmed in vitro with a >100-fold activation window between the acid-activated and intact formulations by an HEK reporter assay and an IFNγ induction assay. ONM-412 showed rapid and complete recovery of IL-12 bioactivity in <10 minutes after acid-activation while MMP demasking of a prodrug required overnight incubation and compromised potency. In vivo, mice treated with muONM-412 demonstrated significantly improved tolerability compared to unencapsulated IL-12Fc: body weight loss was reduced, no liver toxicity was observed, and plasma IFNγ levels were >1,000-fold lower. muONM-412 induced tumor immune remodeling, with increased infiltration by IFNγ+ and GzmB+ CD8 T and NK cells, and demonstrated strong dose-responsive anti-tumor efficacy in MC38 tumor-bearing animals. Preliminary results from an on-going study in cynomolgus monkeys suggest ONM-412 is well-tolerated at equivalent doses to those that induced maximum antitumor response in mice. Conclusions: ONM-412 significantly improved tolerability over unencapsulated IL-12Fc and showed potent anti-tumor efficacy in mice. It was well-tolerated in mice and non-human primates, showing potential for clinical translation. Citation Format: Qingtai Su, Stephen Gutowski, Austin Burcham, Bhargavi Allu, Zirong Chen, Fiona Stavros, Ruolan Han, Jason B. Miller, Tian Zhao. Preclinical characterization of ONM-412, an ultra-pH sensitive nanoparticle encapsulated IL-12 fusion protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB438.
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"Vitamin-D-Hormon-Prodrug Alfacalcidol - Die pleiotrope Therapieoption bei renaler Osteopathie." Dialyse aktuell 12, no. 08 (December 1, 2008): 513. http://dx.doi.org/10.1055/s-0028-1104656.
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Zhang, Bingchen, Yuehua Wang, Shengtao Wang, Yan Tang, Zibo Li, Ling Lin, Yifen Wu, and Zhiqiang Yu. "Precise RNA Editing: Cascade Self‐Uncloaking Dual‐Prodrug Nanoassemblies Based on CRISPR/Cas13a for Pleiotropic Immunotherapy of PD‐L1‐Resistant Colorectal Cancer." Advanced Functional Materials, September 3, 2023. http://dx.doi.org/10.1002/adfm.202305630.
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AbstractCRISPR/Cas13a is a powerful genome editing system for RNA knockdown that holds enormous potential for cancer treatment by targeting currently undruggable oncogenes or immune checkpoints. However, the precise intratumoral activation of CRISPR/Cas13a to maximize the therapeutic efficiency while guaranteeing biosafety remains a daunting challenge. Here, a cascade self‐uncloaking nanoassembly (SRC) based on a dual‐prodrug comprising SN38 and Cas13a/RNP is developed, and the external encapsulation is performed by coating with a ROS‐responsive probe, which is stimulated by the tumor microenvironment to achieve the efficient NIR‐II imaging by CH10055 due to disaggregation into single molecules, while the second release of prodrug in the hypoxic environment enables targeted controlled release. SN38 not only induces immunogenic cell death (ICD), but significantly combats the immunosuppressive microenvironment of colorectal cancer in combination with the RNA editing targeting the novel immune checkpoint TIM3 to regulate the cGAS‐STING pathways, resulting in synergistic activation of both innate and adaptive immunity. The treatment of SRC exhibits a tenfold increase in tumor regression of α‐PD‐L1 in PD‐L1‐resistant orthotopic and xenograft models by inducing effective tumor immune infiltration. These results demonstrate the feasibility of using CRISPR/Cas13a in cancer treatment, and SRC holds immense promise as a neoadjuvant strategy for enhancing CRC immunotherapy.
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Zhao, Fangshi, Xiaoyi Wang, Wei Zhu, Dongju Zhao, Caihua Ye, Yanyan Guo, and Yan Dou. "Low-dose pleiotropic radiosensitive nanoformulations for three-pronged radiochemotherapy of hypoxic brain glioblastoma under BOLD/DWI monitoring." Cancer Nanotechnology 14, no. 1 (February 4, 2023). http://dx.doi.org/10.1186/s12645-023-00159-w.
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Abstract Background Hypoxia-mediated radioresistance is the main obstacle to the successful treatment of glioblastoma (GBM). Enhancing hypoxic radiosensitivity and alleviating tumor hypoxia are both effective means to improve therapeutic efficacy, and the combination of the two is highly desirable and meaningful. Results Herein, we construct a low-dose pleiotropic radiosensitive nanoformulation consisting of a high-Z atomic nanocrystal core and mesoporous silica shell, surface-modified with angiopep-2 (ANG) peptide and loaded with nitric oxide (NO) donor and hypoxia-activated prodrug (AQ4N). Benefiting from ANG-mediated transcytosis, this nanoformulation can efficiently cross the BBB and accumulate preferentially in the brain. Low-dose radiation triggers this nanoformulation to exert a three-pronged synergistic therapeutic effect through high-Z-atom-dependent dose deposition enhancement, NO-mediated hypoxia relief, and AQ4N-induced hypoxia-selective killing, thereby significantly inhibiting GBM in situ growth while prolonging survival and maintaining stable body weight in the glioma-bearing mice. Meanwhile, the proposed in vivo 9.4 T BOLD/DWI can realize real-time dynamic assessment of local oxygen supply and radiosensitivity to monitor the therapeutic response of GBM. Conclusions This work provides a promising alternative for hypoxia-specific GBM-targeted comprehensive therapy, noninvasive monitoring, and precise prognosis. Graphical Abstract
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Germann, Ryan. "In-Vitro Effect of Statins on Enterococcus Faecalis." Journal of Dental Health and Oral Research, January 29, 2024, 1–6. http://dx.doi.org/10.46889/jdhor.2024.5102.
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Objective: The aim of this study was to assess the in-vitro efficacy of statin medications on putative Enterococcus faecaelis, as determined by minimum inhibitory concentration. Methods: Enterococcus faecalis 47077 was grown in the presence of simvastatin lactone (prodrug), simvastatin carboxylate (active metabolite), rosuvastatin, pravastatin and fluvastatin. Minimum Inhibitory Concentrations (MICs) were determined by serial broth dilution assays and bacteriostatic activity by observing the effect of statin on growth curves. Results: MICs against E. faecalis were simvastatin lactone (26.1 μg/ml) and fluvastatin (249 μg/ml). The antibacterial effect of simvastatin lactone and fluvastatin was determined to be bacteriostatic. Simvastatin carboxylate, rosuvastatin and pravastatin did not inhibit bacterial growth. Conclusion: The lipophilic statins simvastatin and fluvastatin act as in-vitro bacteriostatic antimicrobial agents against E. faecalis, whereas the hydrophilic statins simvastatin carboxylate, rosuvastatin and pravastatin did not inhibit bacterial growth in-vitro. The suppression of this pathogen may contribute to the known pleiotropic effect of certain statins, in particular simvastatin.
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Faris, Pawan, Sharon Negri, Delia Faris, Francesca Scolari, Daniela Montagna, and Francesco Moccia. "Hydrogen Sulfide (H2S): As A Potent Modulator And Therapeutic Prodrug In Cancer." Current Medicinal Chemistry 30 (January 26, 2023). http://dx.doi.org/10.2174/0929867330666230126100638.
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Abstract: Hydrogen sulfide (H2S) is an endogenous gaseous molecule present in all living organisms and has been traditionally studied for its toxicity. Interestingly, increased understanding of H2S effects in organ physiology has recently shown its relevance as a signalling molecule, with potentially important implications in variety of clinical disorders, including cancer. H2S is primarily produced in mammalian cells under various enzymatic pathways. A developing focus of H2S is a blooming hotspot that studies chemical, biological mechanisms, and therapeutic effects of H2S. Herein, we describe the physiological and biochemical properties of H2S, the enzymatic pathways leading to its endogenous production and its catabolic routes. In addition, we discuss the role of currently known H2S-releasing agents, or H2S donors, including their potential as therapeutic tools. Then we illustrate the mechanisms known to support the pleiotropic effects of H2S, with a particular focus on persulfhydration, which plays a key role in H2S-mediating signalling pathways. We then address the paradoxical role played by H2S in tumour biology and discuss the potential of exploiting H2S levels as novel cancer biomarkers and diagnostic tools. Finally, we describe the most recent preclinical applications focused on assessing the anti-cancer impact of most common H2S-releasing compounds. While the evidence in favour of H2S as an alternative cancer therapy in the field of translational medicine is yet to be clearly provided, application of H2S is emerging as potent anticancer therapies in preclinical trails.
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Gebremariam, Teclegiorgis, Sondus Alkhazraji, Abdullah Alqarihi, Nathan P. Wiederhold, Karen Joy Shaw, Thomas F. Patterson, Scott G. Filler, and Ashraf S. Ibrahim. "Fosmanogepix (APX001) Is Effective in the Treatment of Pulmonary Murine Mucormycosis Due to Rhizopus arrhizus." Antimicrobial Agents and Chemotherapy 64, no. 6 (March 23, 2020). http://dx.doi.org/10.1128/aac.00178-20.
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ABSTRACT Mucormycosis is a life-threatening infection with high mortality that occurs predominantly in immunocompromised patients. Manogepix (MGX) is a novel antifungal that targets Gwt1, a protein involved in an early step in the conserved glycosylphosphotidyl inositol (GPI) posttranslational modification pathway of surface proteins in eukaryotic cells. Inhibition of fungal inositol acylation by MGX results in pleiotropic effects, including inhibition of maturation of GPI-anchored proteins necessary for growth and virulence. MGX has been previously shown to have in vitro activity against some strains of Mucorales. Here, we assessed the in vivo activity of the prodrug fosmanogepix, currently in clinical development for the treatment of invasive fungal infections, against two Rhizopus arrhizus strains with high (4.0 μg/ml) and low (0.25 μg/ml) minimum effective concentration (MEC) values. In both invasive pulmonary infection models, treatment of mice with 78 mg/kg or 104 mg/kg fosmanogepix, along with 1-aminobenzotriazole to enhance the serum half-life of MGX in mice, significantly increased median survival time and prolonged overall survival by day 21 postinfection compared to placebo. In addition, administration of fosmanogepix resulted in a 1 to 2 log reduction in both lung and brain fungal burden. For the 104 mg/kg fosmanogepix dose, tissue clearance and survival were comparable to clinically relevant doses of isavuconazole (ISA), which is FDA approved for the treatment of mucormycosis. These results support continued development of fosmanogepix as a first-in-class treatment for invasive mucormycosis.