A Poly(amino acid)-Based Nanomedicine Strategy: Telomere-Telomerase Axis Targeting and Magnetic Resonance Imaging in Hepatocellular Carcinoma Treatment.

Targeting telomere maintenance has emerged as a promising strategy for hepatocellular carcinoma (HCC) treatment. However, given the duality of the telomere-telomerase axis in telomere maintenance, a comprehensive strategy is urgently needed. Herein, we develop a poly(amino acid) (D-PAAs)-based strategy for spatiotemporal codelivery of telomerase inhibitor, BIBR1523, and AKT inhibitor, isobavachalcone. By leveraging D-PAAs' modifiability, we synthesize polymer-inhibitor conjugates (PB and PI) and a folic acid-decorated tumor-targeting vector (PF). These building blocks undergo micellization to fabricate a codelivery nanomedicine (P-BI@P-FA) by exploiting D-PAAs' noncovalent assembly. P-BI@P-FA improves the pharmacokinetics, tumor selectivity, and bioavailability of small molecule inhibitors and initiates a dual telomere-specific inhibition by combining telomerase deactivation with telomere disruption. Furthermore, a hybrid tumor-targeting magnetic nanosystem is designed using D-PAAs and manganese dioxide to showcase magnetic resonance imaging capacities. Our D-PAAs-based strategy addresses the pressing need for telomere-specific HCC treatment while allowing for diagnostic application, presenting a promising avenue for nanomedicine design.

Structure-guided design fine-tunes pharmacokinetics, tolerability, and antitumor profile of multispecific frizzled antibodies.

Aberrant activation of Wnt/ß-catenin signaling occurs frequently in cancer. However, therapeutic targeting of this pathway is complicated by the role of Wnt in stem cell maintenance and tissue homeostasis. Here, we evaluated antibodies blocking 6 of the 10 human Wnt/Frizzled (FZD) receptors as potential therapeutics. Crystal structures revealed a common binding site for these monoclonal antibodies (mAbs) on FZD, blocking the interaction with the Wnt palmitoleic acid moiety. However, these mAbs displayed gastrointestinal toxicity or poor plasma exposure in vivo. Structure-guided engineering was used to refine the binding of each mAb for FZD receptors, resulting in antibody variants with improved in vivo tolerability and developability. Importantly, the lead variant mAb significantly inhibited tumor growth in the HPAF-II pancreatic tumor xenograft model. Taken together, our data demonstrate that anti-FZD cancer therapeutic antibodies with broad specificity can be fine-tuned to navigate in vivo exposure and tolerability while driving therapeutic efficacy.

Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress.

Tumor cells gain a survival/growth advantage by adapting their metabolism to respond to environmental stress, a process known as metabolic transformation. The best-known aspect of metabolic transformation is the Warburg effect, whereby cancer cells up-regulate glycolysis under aerobic conditions. However, other mechanisms mediating metabolic transformation remain undefined. Here we report that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific metabolic enzyme, may participate in metabolic transformation. CPT1C expression correlates inversely with mammalian target of rapamycin (mTOR) pathway activation, contributes to rapamycin resistance in murine primary tumors, and is frequently up-regulated in human lung tumors. Tumor cells constitutively expressing CPT1C show increased fatty acid (FA) oxidation, ATP production, and resistance to glucose deprivation or hypoxia. Conversely, cancer cells lacking CPT1C produce less ATP and are more sensitive to metabolic stress. CPT1C depletion via siRNA suppresses xenograft tumor growth and metformin responsiveness in vivo. CPT1C can be induced by hypoxia or glucose deprivation and is regulated by AMPKα. Cpt1c-deficient murine embryonic stem (ES) cells show sensitivity to hypoxia and glucose deprivation and altered FA homeostasis. Our results indicate that cells can use a novel mechanism involving CPT1C and FA metabolism to protect against metabolic stress. CPT1C may thus be a new therapeutic target for the treatment of hypoxic tumors.

Risk Prediction for Ischemic Stroke and Transient Ischemic Attack in Patients Without Atrial Fibrillation: A Retrospective Cohort Study.

BACKGROUND: Stroke mainly occurs in patients without atrial fibrillation (AF). This study explored risk prediction models for ischemic stroke and transient ischemic attack (TIA) in patients without AF. METHODS: Three US-based healthcare databases (Truven MarketScan Commercial Claims and Encounters [CCAE], Medicare Supplemental [MDCR], and Optum Clinformatics [Optum]) were used to establish patient cohorts without AF during the index period of 2008-2012. The performance of 2 existing models (CHADS2 and CHA2DS2-VASc) for predicting stroke and TIA was examined by fitting a logistic regression to a training dataset and evaluating predictive accuracy in a validation dataset (area under the curve, AUC) using patients with complete follow-up of 1 or 3 years, separately. RESULTS: The commercial populations were younger and had fewer comorbidities than Medicare-eligible population. The incidence proportions of ischemic stroke and TIA during 1 and 3 years of follow-up were .5% and 1.9% (CCAE), .6% and 2.2% (Optum), and 4.6% and 13.1% (MDCR), respectively. The models performed consistently across all 3 databases, with the AUC ranging from .69 to .77 and from .68 to .73 for 1- and 3-year prediction, respectively. Predictive accuracy was lower than the initial work of CHADS2 evaluation in patients with AF (AUC: .82), but consistent with a subsequent meta-analysis of CHADS2 (.60-.80) and CHA2DS2-VASc performance (.64-.79). CONCLUSION: Although the existing schemes for predicting ischemic stroke and TIA in patients with AF can be applied to patients without AF with comparable predictive accuracy, the evidence suggests that there is room for improvement in these models' performance.

Design and optimization of (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones as potent PLK4 inhibitors with oral antitumor efficacy.

Previous efforts from our laboratory demonstrated that (E)-3-((3-(E)-vinylaryl)-1H-indazol-6-yl)methylene)-indolin-2-ones are potent PLK4 inhibitors with in vivo anticancer efficacy upon IP dosing. As part of a continued effort to develop selective and orally efficacious inhibitors, we examined variations on this theme wherein 'directly-linked' aromatics, pendant from the indazole core, replace the arylvinyl moiety. Herein, we describe the design and optimization of this series which was ultimately superseded by (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones. The latter compounds are potent and selective inhibitors of PLK4 with oral exposure in rodents and in vivo anticancer activity. Compound 13b, in particular, has a bioavailability of 22% and achieved a 96% tumor growth inhibition in an MDA-MB-468 xenograft study.

Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.

BACKGROUND: The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin. METHODS: In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism. RESULTS: In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P<0.001 for noninferiority; P=0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group. CONCLUSIONS: In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. (Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials.gov number, NCT00403767.).

Nanocage structure derived from sulfonated ß-cyclodextrin intercalated layered double hydroxides and selective adsorption for phenol compounds.

Nanocage structures derived from decasulfonated ß-cyclodextrin (SCD) intercalated ZnAl- and MgAl- layered double hydroxides (LDHs) were prepared through calcination-rehydration reactions. The ZnAl- and MgAl-LDH layers revealed different basal spacings (1.51 nm for SCD-ZnAl-LDH and 1.61 nm for SCD-MgAl-LDH) when contacting SCD, while producing similar monolayer and vertical SCD orientations with cavity axis perpendicular to the LDH layer. The structures of the SCD-LDH and carboxymethyl-ß-cyclodextrin (CMCD)-LDH intercalates were fully analyzed and compared, and a structural model for the SCD-LDH was proposed. The thermal stability of SCD after intercalation was remarkably enhanced, with decomposition temperature increased by 230 °C. The adsorption property of the SCD-LDH composites for phenol compounds (the effects of adsorption time and phenol concentration on adsorption) was investigated completely. The monolayer arrangement of the interlayer SCD did not affect the adsorption efficiency toward organic compounds, which verified the highly swelling ability of the layered compounds in solvents. Both composites illustrated preferential adsorptive efficiency for 2,3-dimethylphenol (DMP) in comparison with other two phenols of hydroquinone (HQ) and tert-butyl-phenol (TBP), resulting from appropriate hydrophobicity and steric hindrance of DMP. For the two phenols of HQ and TBP, SCD-MgAl-LDH gave better adsorption capacity compared with SCD-ZnAl-LDH. The double-confinement effect due to the combination of the parent LDH host and intercalated secondary host may impose high selectivity for guests. This kind of nanocage structure may have potential applications as adsorbents, synergistic agents, and storage vessels for particular guests.

Discovery of inhibitors of the mitotic kinase TTK based on N-(3-(3-sulfamoylphenyl)-1H-indazol-5-yl)-acetamides and carboxamides.

TTK kinase was identified by in-house siRNA screen and pursued as a tractable, novel target for cancer treatment. A screening campaign and systematic optimization, supported by computer modeling led to an indazole core with key sulfamoylphenyl and acetamido moieties at positions 3 and 5, respectively, establishing a novel chemical class culminating in identification of 72 (CFI-400936). This potent inhibitor of TTK (IC50=3.6nM) demonstrated good activity in cell based assay and selectivity against a panel of human kinases. A co-complex TTK X-ray crystal structure and results of a xenograft study with TTK inhibitors from this class are described.

Incidence rate of hospitalization and mortality in the first year following initial diagnosis of cardiac amyloidosis in the US claims databases.

OBJECTIVE: This study aimed to determine rates of hospitalization and in-hospital mortality in the first year following amyloidosis diagnosis with cardiac involvement using observational databases. METHODS: Three administrative claims databases, IBM MarketScan® Commercial Claims and Encounters (CCAE), IBM MarketScan® Multi-State Medicare Database (MDCR), and Optum's de-identified Clinformatics® Data Mart Database (Optum) were analyzed. Adults ≥18 years old, with a diagnosis of amyloidosis and evidence of cardiac involvement (i.e. heart failure, heart block, or cardiomyopathy) but no hepatic/renal failure prior to amyloidosis diagnosis were included for analysis. The primary analyses identified patients between 01-01-2010 and 31-12-2017 period. We calculated the rates of hospitalization and in-hospital mortality within 1 year after the initial diagnosis of amyloidosis. A sensitivity analysis was conducted for patients identified in Optum database during 2004-2011 period, which provided additional mortality information. RESULTS: A total of 419, 654, and 922 patients from CCAE, MDCR, and Optum were identified during 2010-2017 period, with mean age of 55.6, 77.8, and 74.2 years, respectively. Within 1 year following initial amyloidosis diagnosis, incidence rates (95% confidence interval [CI]) of hospitalization were 78.4 (66.3, 90.4), 78.6 (69.2, 87.9), and 61.2 (54.4, 68.0) per 100 person-years, rates of in-hospital mortality were 16.5 (11.8, 21.3), 8.4 (5.7, 11.0), and 17.7 (14.5, 21.0) per 100 person-years, in CCAE, MDCR, and Optum, respectively. The mortality rate from the sensitivity analysis among patients identified in Optum 2004-2011 period was higher compared with Optum 2010-2017 period. CONCLUSIONS: The results from this study indicate that amyloidosis with cardiac involvement is a condition with high rates of hospitalization and mortality in the first year after initial diagnosis. Future studies are needed to further evaluate the outcomes within the subtypes of amyloidosis and understand the risk factors associated with poor prognoses.

Direct conversion of wet sewage sludge to carbon catalyst for sulfamethoxazole degradation through peroxymonosulfate activation.

The high moisture content of wet sewage sludge generated from wastewater treatment process not only brings high cost of sewage disposal, but also limits its utilization as resource. In this study, an efficient strategy of directly utilizing wet sludge to develop advanced carbocatalyst via a hydrothermal coupled pyrolysis process was proposed. The possible application of as-synthesized carbocatalyst was evaluated by activating peroxymonosulfate (PMS) to degrade a model pollutant of sulfamethoxazole (SMX). Experimental results showed that about 100% of SMX and 59% of total organic carbon (TOC) could be removed within 15 min. Moisture content in wet sludge also affected the performances of as-obtained carbocatalysts. Further studies verified that singlet oxygen (1O2) dominated SMX degradation, which was generated in the process of PMS activation by CO groups on the surface of carbocatalyst. In the preliminary ecological test, a lower ecotoxicity of SMX degradation solution compared with the original solution was observed. This study demonstrated the feasibility of directly utilizing wet sludge for advanced carbocatalyst fabrication, which provided another solution for wet sludge treatment and utilization.

Gamma-synuclein is an adipocyte-neuron gene coordinately expressed with leptin and increased in human obesity.

Recently, we characterized tumor suppressor candidate 5 (Tusc5) as an adipocyte-neuron PPARgamma target gene. Our objective herein was to identify additional genes that display distinctly high expression in fat and neurons, because such a pattern could signal previously uncharacterized functional pathways shared in these disparate tissues. gamma-Synuclein, a marker of peripheral and select central nervous system neurons, was strongly expressed in white adipose tissue (WAT) and peripheral nervous system ganglia using bioinformatics and quantitative PCR approaches. Gamma-synuclein expression was determined during adipogenesis and in subcutaneous (SC) and visceral adipose tissue (VAT) from obese and nonobese humans. Gamma-synuclein mRNA increased from trace levels in preadipocytes to high levels in mature 3T3-L1 adipocytes and decreased approximately 50% following treatment with the PPARgamma agonist GW1929 (P < 0.01). Because gamma-synuclein limits growth arrest and is implicated in cancer progression in nonadipocytes, we suspected that expression would be increased in situations where WAT plasticity/adipocyte turnover are engaged. Consistent with this postulate, human WAT gamma-synuclein mRNA levels consistently increased in obesity and were higher in SC than in VAT; i.e. they increased approximately 1.7-fold in obese Pima Indian adipocytes (P = 0.003) and approximately 2-fold in SC and VAT of other obese cohorts relative to nonobese subjects. Expression correlated with leptin transcript levels in human SC and VAT (r = 0.887; P < 0.0001; n = 44). Gamma-synuclein protein was observed in rodent and human WAT but not in negative control liver. These results are consistent with the hypothesis that gamma-synuclein plays an important role in adipocyte physiology.

Bias and variance evaluation of QT interval correction methods.

There is an increasing regulatory emphasis on assessing drug-induced QT interval prolongation. Since QT interval is correlated with heart rate (HR), assessment of drug-induced QT interval prolongation should be made at a standardized HR, resulting in the need to correct QT interval (QTc) for HR. This study investigates the statistical properties of QTc intervals using individual based correction (IBC), population based correction (PBC), or fixed correction (FC) methods under both the linear and log-linear regression models for the QT-RR relationship where RR is the time elapsing between two consecutive heart beats (inversely related to HR through RR = 60/HR). This study shows that QTc intervals using PBC and FC methods are conditionally biased. The QTc interval using the IBC method is conditionally unbiased under the linear regression model, but is conditionally biased under the log-linear regression model. It also shows that under both the linear and log-linear regression models, the conditional variances of the QTc intervals using the three correction methods satisfy the order FC < or = PBC < or = IBC. Suggestions for analyzing QT intervals based on these findings are discussed.

Influence of age on the pharmacokinetics, pharmacodynamics, efficacy, and safety of rivaroxaban.

OBJECTIVE: Atrial fibrillation, peripheral and coronary artery disease, and venous thromboembolism are major risk factors for stroke, disability, and death in the rapidly growing older (≥ 65 years.) population. In the absence of clear guidelines on the appropriate use of the newer non-vitamin K antagonist oral anticoagulants in this population, this study specifically reviews the available literature for rivaroxaban and the impact of age that may affect the pharmacokinetics, pharmacodynamics, efficacy, and safety of this anticoagulant. METHODS: This review includes a summary of data obtained from the available literature concerning both older healthy subjects and older patients with various aspects of cardiovascular disease enrolled in rivaroxaban clinical trials and data from real world evidence studies. RESULTS: Evaluation of the clinical pharmacology in healthy, older adults reveal no clinically relevant effect of age on rivaroxaban pharmacokinetics and pharmacodynamics. Population pharmacokinetic studies in older patients with thromboembolic diseases suggest a moderate effect of increasing age on rivaroxaban clearance, albeit not clinically significant. Additionally, sub-group analyses from large, phase 3 clinical trials demonstrate consistent efficacy and safety in the older patient population vs the overall population. These findings are further supported by real-world evidence studies. CONCLUSION: A favorable clinical profile with rivaroxaban was observed across age sub-groups, supporting the premise that dosing in older adults does not necessitate adjustment. However, it is prudent that a cautious and individualized approach is taken for treatment with any anticoagulant in older adults.

Efficacy, safety and early response of paliperidone extended-release tablets (paliperidone ER): results of a 6-week, randomized, placebo-controlled study.

BACKGROUND: Paliperidone extended-release tablet (paliperidone ER) is an oral psychotropic agent developed for schizophrenia treatment. Paliperidone (9-OH-risperidone, metabolite of risperidone), when used with OROS technology has a unique pharmacokinetic profile undergoing limited hepatic metabolism. METHODS: The efficacy and safety of once-daily paliperidone ER (3 mg, 9 mg and 15 mg) were compared with placebo in 618 patients with acute schizophrenia in a 6-week, multicenter, double-blind, randomized, parallel-group study. An assay sensitivity group with known efficacy was included to confirm trial validity (olanzapine 10 mg). RESULTS: All doses of paliperidone ER demonstrated significant improvements in PANSS total and PANSS factors scores (p<0.05) and in personal and social functioning (p<0.001) compared with placebo. Symptom improvement has been observed at the first observation assessment (Day 4) (p<0.001) compared with placebo, suggesting a rapid onset of action for paliperidone ER. Paliperidone ER was associated with a low incidence of treatment-emergent adverse events. The incidence of movement disorder-related adverse events and rating scale scores were similar in the paliperidone ER 3 mg and placebo groups and increased with dose. Increases in prolactin plasma levels and dose-related increases in body weight (<2 kg) were observed; there were no significant changes in serum lipid or glucose levels. CONCLUSION: In this study, all doses of paliperidone ER were effective in significantly improving the symptoms of schizophrenia and personal and social functioning and were generally well tolerated. As such, paliperidone ER may provide a valuable new treatment option for patients with schizophrenia.

Angelicin inhibits liver cancer growth in vitro and in vivo.

Previous studies have reported that angelicin exerted antiproliferative effects on several types of tumor cell. However, to the best of our knowledge, the effects of angelicin monotherapy on human liver cancer remain to be investigated. In the present study, the antitumor activity of angelicin was evaluated in vitro and in vivo, and the molecular mechanisms underlying its effects were investigated. The present results revealed that angelicin induced apoptosis in liver cancer cells in a dose­ and time­dependent manner. Furthermore, in HepG2 and Huh­7 cells, angelicin­induced apoptosis was demonstrated to be mitochondria dependent, involving the phosphatidylinositol­4,5­bisphosphate 3­kinase/RAC­α serine/threonine-protein kinase signaling pathway. In addition, administration of angelicin to mice bearing liver tumor xenografts inhibited tumor growth, without producing significant secondary adverse effects. These results suggested that angelicin may have potential as a novel therapeutic agent for the treatment of patients with liver cancer.

A proposed statistical framework for the management of subgroup analyses for large clinical trials.

Planned and unplanned subgroup analyses of large clinical trials are frequently performed and the results are sometimes difficult to interpret. The source of a nominal significant finding may come from a true signal, variation of the clinical trial outcome or the observed data structure. Quantitative assessment is critical to the interpretation of the totality of the clinical data. In this article we provide a general framework to manage subgroup analyses and to interpret the findings through a set of supplement analyses to planned main (primary and secondary) analyses, as an alternative to the commonly used multiple comparison framework. The proposed approach collectively and coherently utilizes several quantitative methods and enhances the credibility and interpretability of subgroup analyses. A case study is used to illustrate the application of the proposed method.

The discovery of Polo-like kinase 4 inhibitors: design and optimization of spiro[cyclopropane-1,3'[3H]indol]-2'(1'H).ones as orally bioavailable antitumor agents.

Polo-like kinase 4 (PLK4), a unique member of the polo-like kinase family of serine-threonine kinases, is a master regulator of centriole duplication that is important for maintaining genome integrity. Overexpression of PLK4 is found in several human cancers and is linked with a predisposition to tumorigenesis. Previous efforts to identify potent and efficacious PLK4 inhibitors resulted in the discovery of (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones, which are superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones reported herein. Optimization of this new cyclopropane-linked series was based on a computational model of a PLK4 X-ray structure and SAR attained from the analogous alkenelinked series. The racemic cyclopropane-linked compounds showed PLK4 affinity and antiproliferative activity comparable to their alkene-linked congeners with improved hysicochemical, ADME, and pharmacokinetic properties. Positive xenograft results from the MDA-MB-468 human breast cancer xenograft model for compound 18 support the investigation of PLK4 inhibitors as anticancer therapeutics. A PLK4 X-ray co-structure with racemate 18 revealed preferential binding of the 1R,2S enantiomer to the PLK4 kinase domain.

The discovery of Polo-like kinase 4 inhibitors: identification of (1R,2S).2-(3-((E).4-(((cis).2,6-dimethylmorpholino)methyl)styryl). 1H.indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (CFI-400945) as a potent, orally active antitumor agent.

Previous publications from our laboratory have introduced novel inhibitors of Polo-like kinase 4 (PLK4), a mitotic kinase identified as a potential target for cancer therapy. The search for potent and selective PLK4 inhibitors yielded (E)-3-((1Hindazol-6-yl)methylene)indolin-2-ones, which were superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones, e.g., 3. The later scaffold confers improved drug-like properties and incorporates two stereogenic centers. This work reports the discovery of a novel one-pot double SN2 displacement reaction for the stereoselective installation of the desired asymmetric centers and confirms the stereochemistry of the most potent stereoisomer, e.g., 44. Subsequent work keys on the optimization of the oral exposure of nanomolar PLK4 inhibitors with potent cancer cell growth inhibitory activity. A short list of compounds with superior potency and pharmacokinetic properties in rodents and dogs was studied in mouse models of tumor growth. We conclude with the identification of compound 48 (designated CFI-400945) as a novel clinical candidate for cancer therapy.

Synthetic antibodies with a human framework that protect mice from lethal Sudan ebolavirus challenge.

The ebolaviruses cause severe and rapidly progressing hemorrhagic fever. There are five ebolavirus species; although much is known about Zaire ebolavirus (EBOV) and its neutralization by antibodies, little is known about Sudan ebolavirus (SUDV), which is emerging with increasing frequency. Here we describe monoclonal antibodies containing a human framework that potently inhibit infection by SUDV and protect mice from lethal challenge. The murine antibody 16F6, which binds the SUDV envelope glycoprotein (GP), served as the starting point for design. Sequence and structural alignment revealed similarities between 16F6 and YADS1, a synthetic antibody with a humanized scaffold. A focused phage library was constructed and screened to impart 16F6-like recognition properties onto the YADS1 scaffold. A panel of 17 antibodies were characterized and found to have a range of neutralization potentials against a pseudotype virus infection model. Neutralization correlated with GP binding as determined by ELISA. Two of these clones, E10 and F4, potently inhibited authentic SUDV and conferred protection and memory immunity in mice from lethal SUDV challenge. E10 and F4 were further shown to bind to the same epitope on GP as 16F6 with comparable affinities. These antibodies represent strong immunotherapeutic candidates for treatment of SUDV infection.