ABSTRACT
The iminosugar UV-4 is a broad-spectrum antiviral drug candidate with activity in vitro and in vivo against multiple, diverse viruses. The toxicological profile of UV-4, dosed as the hydrochloride salt, was evaluated in single-dose and repeat-dose oral toxicity studies in mice, rats, dogs, and non-human primates (NHP). No moribundity or deaths were associated with the drug up to the maximum tolerated dose. No treatment-related adverse effects were observed following single oral doses in dogs, rats, and mice up to 250, 400, 1000 mg/kg, respectively, and in NHP up to 180 mg/kg administered three times daily for 10 days. UV-4-related findings were generally seen at higher doses after 7- or 14-day exposure. The most common clinical pathology findings (increase in aspartate aminotransferase and decreased platelet count) were consistently found across species and each appeared dose related. The kidney, mesenteric lymph nodes, stomach including gastrointestinal tract, and thymus were identified as target organs in mice, rats, and dogs. In 14-day repeat-dose toxicology studies in mice and dogs conducted in compliance with Good Laboratory Practice regulations, the dog was considered to be the most sensitive species to UV-4 exposure based on the treatment-related adverse effects noted in the identified target organs. The results of these studies demonstrate the safety profile of UV-4 hydrochloride and supported the selection of starting and maximal doses for a single ascending dose first-in-human clinical study.
Subject(s)
Antiviral Agents , Drugs, Investigational , Administration, Oral , Animals , Antiviral Agents/therapeutic use , Antiviral Agents/toxicity , Dogs , Drugs, Investigational/toxicity , Maximum Tolerated Dose , Mice , RatsABSTRACT
UV-4 (N-(9-methoxynonyl)-1-deoxynojirimycin) is a broad-spectrum antiviral drug candidate with demonstrated activity in vitro and in vivo against multiple, diverse viruses. Nonclinical safety pharmacology studies were conducted to support the filing of an Investigational New Drug (IND) application. Preliminary in vitro pharmacology testing evaluating potential for binding to "off-target" receptors and enzymes indicated no significant liability for advanced development of UV-4. The safety pharmacology of UV-4 was evaluated in the in vitro human ether-à-go-go-related gene (hERG) assay, in a central nervous system (CNS) study in the mouse (modified Irwin test), in a respiratory safety study in conscious mice using whole body plethysmography, and in a cardiovascular safety study in conscious, radiotelemetry-instrumented beagle dogs. There were no observed adverse treatment-related effects following administration of UV-4 as the hydrochloride salt in the hERG potassium channel assay, on respiratory function, in the CNS study, or in the cardiovascular assessment. Treatment-related cardiovascular effect of decreased arterial pulse pressure after 50 or 200 mg of UV-4/kg was the only change outside the normal range, and all hemodynamic parameters returned to control levels by the end of the telemetry recording period. These nonclinical safety pharmacology assessments support the evaluation of this host-targeted broad-spectrum antiviral drug candidate in clinical studies.
Subject(s)
Cardiovascular System , Drug-Related Side Effects and Adverse Reactions , Animals , Antiviral Agents/toxicity , Dogs , Drug Evaluation, Preclinical , Drugs, Investigational , Mice , TelemetryABSTRACT
Dengue fever is a leading cause of illness and mortality in the tropics and subtropics. There are no therapeutics currently available and a recently approved vaccine is not very efficacious demanding an urgent need to develop an effective antiviral. The path to successful dengue drug development depends on availability of relevant preclinical testing models and better understanding of dengue pathogenesis. In recent years, efforts to develop dengue therapeutics have focused on both repurposing approved drugs as well as discovery of new chemical entities that act via virus or host targeted mechanisms. Here, we discuss the various innovative approaches, their outcome, and the lessons gleaned from the development efforts.
Subject(s)
Antiviral Agents/pharmacology , Dengue Virus/physiology , Dengue/drug therapy , Drug Discovery/trends , Animals , Antiviral Agents/chemistry , Dengue/virology , Dengue Virus/drug effects , Dengue Virus/genetics , Drug Discovery/methods , HumansABSTRACT
UNLABELLED: The host-targeted antiviral drug UV-4B reduces viral replication and promotes survival in a mouse model of experimental dengue virus (DENV) infection. UV-4B is an iminosugar that inhibits the α-glucosidase family of enzymes and subsequently the folding of glycosylated proteins, both viral and host. Here, we utilized next-generation sequencing to investigate evolution of a flavivirus under selective pressure by a host-targeted antiviral in vivo. In viral populations recovered from UV-4B-treated mice, there was a significant increase in the number of single-nucleotide polymorphisms (SNPs) and the ratio of nonsynonymous to synonymous SNPs compared to findings in viral populations from vehicle-treated mice. The strongest evidence of positive selection was in the glycosylated membrane protein, thereby providing in vivo validation of the mechanism of action of an iminosugar. In addition, mutations in glycosylated proteins were present only in drug-treated mice after a single passage. However, the bulk of the other mutations were present in both populations, indicating nonspecific selective pressure. Together with the continued control of viremia by UV-4B, these findings are consistent with the previously predicted high genetic barrier to escape mutations in host-targeted antivirals. IMPORTANCE: Although hundreds of millions of people are infected with DENV every year, there is currently no approved vaccine or antiviral therapy. UV-4B has demonstrated antiviral activity against DENV and is expected to enter clinical trials soon. Therefore, it is important to understand the mechanisms of DENV resistance to UV-4B. Host-targeted antivirals are thought to have a higher genetic barrier to escape mutants than directly acting antivirals, yet there are very few published studies of viral evolution under host-targeted antivirals. No study to date has described flavivirus evolution in vivo under selective pressure by a host-based antiviral drug. We present the first in vivo study of the sequential progression of viral evolution under selective pressure by a host-targeted antiviral compound. This study bolsters support for the clinical development of UV-4B as an antiviral drug against DENV, and it provides a framework to compare how treatment with other host-targeted antiflaviviral drugs in humans and different animal models influence viral genetic diversity.
Subject(s)
Antiviral Agents/pharmacology , Dengue Virus/drug effects , Dengue Virus/genetics , Dengue/drug therapy , Dengue/virology , Animals , Dengue Virus/physiology , Disease Models, Animal , Evolution, Molecular , Genetic Variation , Host-Pathogen Interactions/drug effects , Humans , Imino Sugars/pharmacology , Mice , Mice, 129 Strain , Mice, Knockout , Mutation , Polymorphism, Single Nucleotide , Selection, Genetic , Viral Proteins/genetics , Virus Replication/drug effectsABSTRACT
Individuals with glucose 6-phosphate dehydrogenase (G6PD) deficiency are at risk for the development of hemolytic anemia when given 8-aminoquinolines (8-AQs), an important class of antimalarial/antiinfective therapeutics. However, there is no suitable animal model that can predict the clinical hemolytic potential of drugs. We developed and validated a human (hu)RBC-SCID mouse model by giving nonobese diabetic/SCID mice daily transfusions of huRBCs from G6PD-deficient donors. Treatment of SCID mice engrafted with G6PD-deficient huRBCs with primaquine, an 8-AQ, resulted in a dose-dependent selective loss of huRBCs. To validate the specificity of this model, we tested known nonhemolytic antimalarial drugs: mefloquine, chloroquine, doxycycline, and pyrimethamine. No significant loss of G6PD-deficient huRBCs was observed. Treatment with drugs known to cause hemolytic toxicity (pamaquine, sitamaquine, tafenoquine, and dapsone) resulted in loss of G6PD-deficient huRBCs comparable to primaquine. This mouse model provides an important tool to test drugs for their potential to cause hemolytic toxicity in G6PD-deficient populations.
Subject(s)
Anemia, Hemolytic/diagnosis , Erythrocyte Transfusion/methods , Glucosephosphate Dehydrogenase Deficiency/therapy , Primaquine/therapeutic use , Aminoquinolines/adverse effects , Aminoquinolines/therapeutic use , Anemia, Hemolytic/blood , Anemia, Hemolytic/chemically induced , Animals , Antimalarials/adverse effects , Antimalarials/therapeutic use , Chloroquine/adverse effects , Chloroquine/therapeutic use , Combined Modality Therapy , Dapsone/adverse effects , Dapsone/therapeutic use , Dose-Response Relationship, Drug , Doxycycline/adverse effects , Doxycycline/therapeutic use , Drug Evaluation, Preclinical/methods , Erythrocyte Count , Female , Glucosephosphate Dehydrogenase Deficiency/blood , Humans , Mefloquine/adverse effects , Mefloquine/therapeutic use , Mice , Mice, Inbred NOD , Mice, SCID , Primaquine/adverse effects , Pyrimethamine/adverse effects , Pyrimethamine/therapeutic use , Reproducibility of Results , Sensitivity and Specificity , Transplantation, HeterologousABSTRACT
Primaquine (PQ) remains the sole available drug to prevent relapse of Plasmodium vivax malaria more than 60 years after licensure. While this drug was administered as a racemic mixture, prior studies suggested a pharmacodynamic advantage based on differential antirelapse activity and/or toxicities of its enantiomers. Oral primaquine enantiomers prepared using a novel, easily scalable method were given for 7 days to healthy rhesus macaques in a dose-rising fashion to evaluate their effects on the blood, liver, and kidneys. The enantiomers were then administered to Plasmodium cynomolgi-infected rhesus macaques at doses of 1.3 and 0.6 mg/kg of body weight/day in combination with chloroquine. The (-)-PQ enantiomer had higher clearance and apparent volume of distribution than did (+)-PQ and was more extensively converted to the carboxy metabolite. There is evidence for differential oxidative stress with a concentration-dependent rise in methemoglobin (MetHgb) with increasing doses of (+)-PQ greater than that seen for (-)-PQ. There was a marked, reversible hepatotoxicity in 2 of 3 animals dosed with (-)-PQ at 4.5 mg/kg. (-)-PQ in combination with chloroquine was successful in preventing P. cynomolgi disease relapse at doses of 0.6 and 1.3 mg/kg/day, while 1 of 2 animals receiving (+)-PQ at 0.6 mg/kg/day relapsed. While (-)-PQ was also associated with hepatotoxicity at higher doses as seen previously, this has not been identified as a clinical concern in humans during >60 years of use. Limited evidence for increased MetHgb generation with the (+) form in the rhesus macaque model suggests that it may be possible to improve the therapeutic window for hematologic toxicity in the clinic by separating primaquine into its enantiomers.
Subject(s)
Antimalarials/pharmacokinetics , Chloroquine/pharmacology , Malaria/drug therapy , Plasmodium cynomolgi/drug effects , Primaquine/pharmacokinetics , Animals , Antimalarials/blood , Antimalarials/chemistry , Antimalarials/pharmacology , Disease Models, Animal , Drug Administration Schedule , Drug Therapy, Combination , Humans , Kidney/drug effects , Liver/drug effects , Macaca mulatta , Malaria/blood , Malaria/parasitology , Malaria, Vivax , Male , Methemoglobin/metabolism , Oxidative Stress , Plasmodium cynomolgi/growth & development , Plasmodium vivax , Primaquine/blood , Primaquine/chemistry , Primaquine/pharmacology , Recurrence , StereoisomerismABSTRACT
COVID-19, which broke out globally in 2019, is an infectious disease caused by a novel strain of coronavirus, and its spread is highly contagious and concealed. Environmental vectors play an important role in viral infection and transmission, which brings new difficulties and challenges to disease prevention and control. In this paper, a type of differential equation model is constructed according to the spreading functions and characteristics of exposed individuals and environmental vectors during the virus infection process. In the proposed model, five compartments were considered, namely, susceptible individuals, exposed individuals, infected individuals, recovered individuals, and environmental vectors (contaminated with free virus particles). In particular, the re-positive factor was taken into account (i.e., recovered individuals who have lost sufficient immune protection may still return to the exposed class). With the basic reproduction number R0 of the model, the global stability of the disease-free equilibrium and uniform persistence of the model were completely analyzed. Furthermore, sufficient conditions for the global stability of the endemic equilibrium of the model were also given. Finally, the effective predictability of the model was tested by fitting COVID-19 data from Japan and Italy.
Subject(s)
COVID-19 , Communicable Diseases , Humans , COVID-19/epidemiology , Japan/epidemiology , Italy/epidemiology , Basic Reproduction NumberABSTRACT
Together with the NS5 polymerase, the NS3 helicase has a pivotal function in flavivirus RNA replication and constitutes an important drug target. We captured the dengue virus NS3 helicase at several stages along the catalytic pathway including bound to single-stranded (ss) RNA, to an ATP analogue, to a transition-state analogue and to ATP hydrolysis products. RNA recognition appears largely sequence independent in a way remarkably similar to eukaryotic DEAD box proteins Vasa and eIF4AIII. On ssRNA binding, the NS3 enzyme switches to a catalytic-competent state imparted by an inward movement of the P-loop, interdomain closure and a change in the divalent metal coordination shell, providing a structural basis for RNA-stimulated ATP hydrolysis. These structures demonstrate for the first time large quaternary changes in the flaviviridae helicase, identify the catalytic water molecule and point to a beta-hairpin that protrudes from subdomain 2, as a critical element for dsRNA unwinding. They also suggest how NS3 could exert an effect as an RNA-anchoring device and thus participate both in flavivirus RNA replication and assembly.
Subject(s)
Adenosine Triphosphate/metabolism , Protein Structure, Quaternary , RNA Helicases/chemistry , RNA Helicases/metabolism , RNA/metabolism , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Models, Molecular , Serine Endopeptidases/chemistry , Serine Endopeptidases/metabolismABSTRACT
UV-4 (N-(9-methoxynonyl)-1-deoxynojirimycin) is a host-targeted antiviral agent, which targets mammalian proteins (endoplasmic reticulum glucosidases) rather than virally encoded proteins. This mechanism confers both broad-spectrum activity and low potential for generation of viral drug resistance mutations. Reproductive and developmental studies of UV-4 evaluated effects on fertility and early embryonic development in rats, embryo-fetal development in rats and rabbits, and pre- and postnatal development including maternal function in rats. All reproductive and developmental studies conducted achieved dose levels where parental toxicity (generally decreased body weight, decreased food consumption and adverse clinical signs) were observed. Toxicokinetic evaluations confirmed UV-4 crossed the placenta exposing fetal rats and rabbits in utero. Adverse findings in reproductive and developmental studies included decreases in sperm motility with histopathology correlates, visceral and skeletal malformations, changes in eye opening, air drop reflex, vaginal opening and preputial separation. The combined results of the fertility and early embryonic developmental study and pre- and postnatal study suggested that there may be an increased risk for male fertility. These effects are similar to those reported in pre-clinical studies of the structurally related drug Miglustat (N-butyl-1-deoxynojirimycin), therefore UV-4 may have risk of developmental or reproductive adverse outcomes in humans similar to existing approved agents in this drug class.
Subject(s)
Reproduction , Sperm Motility , Pregnancy , Female , Humans , Male , Rats , Rabbits , Animals , Rats, Sprague-Dawley , Dose-Response Relationship, Drug , Fertility , Body Weight , MammalsABSTRACT
BACKGROUND: UV-4 (N-(9'-methoxynonyl)-1-deoxynojirimycin, also called MON-DNJ) is an iminosugar small-molecule oral drug candidate with in vitro antiviral activity against diverse viruses including dengue, influenza, and filoviruses and demonstrated in vivo efficacy against both dengue and influenza viruses. The antiviral mechanism of action of UV-4 is through inhibition of the host endoplasmic reticulum-resident α-glucosidase 1 and α-glucosidase 2 enzymes. This inhibition prevents proper glycan processing and folding of virus glycoproteins, thereby impacting virus assembly, secretion, and the fitness of nascent virions. METHODOLOGY/PRINCIPAL FINDINGS: Here we report a first-in-human, single ascending dose Phase 1a study to evaluate the safety, tolerability, and pharmacokinetics of UV-4 hydrochloride (UV-4B) in healthy subjects (ClinicalTrials.gov Identifier NCT02061358). Sixty-four subjects received single oral doses of UV-4 as the hydrochloride salt equivalent to 3, 10, 30, 90, 180, 360, 720, or 1000 mg of UV-4 (6 subjects per cohort), or placebo (2 subjects per cohort). Single doses of UV-4 hydrochloride were well tolerated with no serious adverse events or dose-dependent increases in adverse events observed. Clinical laboratory results, vital signs, and physical examination data did not reveal any safety signals. Dose-limiting toxicity was not observed; the maximum tolerated dose of UV-4 hydrochloride in humans has not yet been determined (>1000 mg). UV-4 was rapidly absorbed and distributed after dosing with the oral solution formulation used in this study. Median time to reach maximum plasma concentration ranged from 0.5-1 hour and appeared to be independent of dose. Exposure increased approximately in proportion with dose over the 333-fold dose range. UV-4 was quantifiable in pooled urine over the entire collection interval for all doses. CONCLUSIONS/SIGNIFICANCE: UV-4 is a host-targeted broad-spectrum antiviral drug candidate. At doses in humans up to 1000 mg there were no serious adverse events reported and no subjects were withdrawn from the study due to treatment-emergent adverse events. These data suggest that therapeutically relevant drug levels of UV-4 can be safely administered to humans and support further clinical development of UV-4 hydrochloride or other candidate antivirals in the iminosugar class. TRIAL REGISTRATION: ClinicalTrials.gov NCT02061358 https://clinicaltrials.gov/ct2/show/NCT02061358.
Subject(s)
Dengue , alpha-Glucosidases , 1-Deoxynojirimycin/adverse effects , Antiviral Agents/pharmacology , Area Under Curve , Dengue/drug therapy , Dose-Response Relationship, Drug , Double-Blind Method , Healthy Volunteers , Humans , alpha-Glucosidases/metabolism , alpha-Glucosidases/therapeutic useABSTRACT
In this paper, a delayed phytoplankton-zooplankton system with the coeffcient depending on delay is investigated. Firstly, it gives the nonnegative and boundedness of solutions of the delay differential equations. Secondly, it gives the asymptotical stability properties of equilibria in the absence of time delay. Then in the presence of time delay, the existence of local Hopf bifurcation is discussed when the delay changes. In addition to that, the stability of periodic solution and bifurcation direction are also obtained through the use of central manifold theory. Furthermore, he global continuity of the local Hopf bifurcation is discussed by using the global Hopf bifurcation result of FDE. At last, some numerical simulations are presented to show the rationality of theoretical analyses.
Subject(s)
Phytoplankton/physiology , Zooplankton/physiology , Algorithms , Animals , Computer Simulation , Eutrophication , Models, Biological , Population Dynamics , Reproducibility of Results , Time FactorsABSTRACT
A stochastic SIR model with vertical transmission and vaccination is proposed and investigated in this paper. The threshold dynamics are explored when the noise is small. The conditions for the extinction or persistence of infectious diseases are deduced. Our results show that large noise can lead to the extinction of infectious diseases which is conducive to epidemic diseases control.
Subject(s)
Communicable Disease Control , Infectious Disease Transmission, Vertical/statistics & numerical data , Models, Biological , Vaccination/statistics & numerical data , Computer Simulation , Disease Eradication/statistics & numerical data , Humans , Stochastic ProcessesABSTRACT
The 30th International Conference on Antiviral Research (ICAR) was held in Atlanta, GA, USA from May 18 to 21, 2017. This report provides an account of award lectures, invited keynote addresses and oral presentations during the meeting. The 2017 Gertrude Elion Memorial Lecture Award by Michael Sofia highlighted one of the most important accomplishments in recent drug discovery in antiviral research, the identification of the hepatitis C virus direct-acting antiviral sofosbuvir and new alternatives to combat hepatitis B virus (HBV) infection. The Antonín Holý Lecture Award by David Chu on medicinal chemistry provided an overview of early developments of nucleoside analogs for the treatment of HIV and varicella zoster virus infection and how this knowledge serves to develop new drugs targeting HBV. Priscilla Yang gave the first ISAR Women in Science lecture. She reported on pharmacological validation of new antiviral targets for dengue, Zika and other flaviviruses. The William Prusoff Young Investigator Lecture Award by Maaike Everts described the Alabama Drug Discovery Alliance and the Antiviral Drug Discovery and Development Consortium, and how they are helping to accelerate the development of new antivirals. The 30th ICAR was a success in promoting new discoveries in antiviral drug development and research. The 31st ICAR will be held in Porto, Portugal, June 11-15, 2018.
Subject(s)
Antiviral Agents , Chemistry, Pharmaceutical , Drug Discovery , Dengue/drug therapy , Hepatitis B/drug therapy , Humans , Zika Virus Infection/drug therapyABSTRACT
Infectious diseases caused by flaviviruses are important emerging public health concerns and new vaccines and therapeutics are urgently needed. The NS3 protein from flavivirus is a multifunctional protein with protease, helicase and nucleoside 5' triphosphatase activities (NTPase). Thus, NS3 plays a crucial role in viral replication and represents an interesting target for the development of specific antiviral inhibitors. We have solved the structure of an enzymatically active fragment of the dengue virus NTPase/ helicase C-terminal catalytic domain in several related crystal forms. The structure is composed of three domains, bears an asymmetric distribution of charges and comprises a tunnel large enough to accommodate single strand RNA. A concave face formed by domains 2 and 3 is proposed to bind a nucleic acid duplex substrate. Comparison of the various copies of dengue and yellow fever virus NS3 NTPase/helicase catalytic domains reveals mobile regions of the enzyme. Such dynamic behaviour is likely to be coupled with directional translocation along the single strand nucleic acid substrate during strand separation. We used structure-based site directed mutagenesis to identify regions of the enzyme that are crucial for its ATPase or nucleic acid duplex unwinding activity.
Subject(s)
DNA Helicases/chemistry , Dengue Virus/enzymology , Drug Design , Enzyme Inhibitors/chemistry , Nucleoside-Triphosphatase/chemistry , Viral Nonstructural Proteins/chemistry , Binding Sites , Catalytic Domain , Crystallization , DNA Helicases/antagonists & inhibitors , DNA Helicases/genetics , Dimerization , Models, Molecular , Mutagenesis, Site-Directed , Nucleoside-Triphosphatase/antagonists & inhibitors , Nucleoside-Triphosphatase/genetics , RNA Helicases/chemistry , RNA Helicases/genetics , RNA Helicases/metabolism , Serine Endopeptidases/chemistry , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolismABSTRACT
With the incidence of dengue fever increasing all over the world, there is an urgent need for therapies. While drug discovery for any disease is a long and difficult process with uncertain success, dengue fever poses an additional complication in that most of the target patient population is young and lives in developing countries with very limited health care budgets. Recent progress in drug discovery for dengue and an analysis of approaches toward hepatitis C virus (HCV) therapeutics suggest that NS5 polymerase is the most promising target for dengue. Moreover such inhibitors may be useful for several other flaviviral diseases. NS3 proteases will be more challenging targets, especially if oral delivery is desired. Recent work has shown that potent inhibitors can be designed readily, but optimization of pharmacokinetic parameters will probably be a long an arduous task, especially since the primary binding pockets prefer to bind basic amino acids. NS3 helicase can also be considered a viable drug target for flaviviral diseases. It has however proved to be a challenging for HCV and selectivity issues versus human helicases must be overcome.
Subject(s)
Antiviral Agents/therapeutic use , Flavivirus/drug effects , Serine Proteinase Inhibitors/therapeutic use , Viral Proteins/antagonists & inhibitors , Animals , Drug Design , Flavivirus/enzymology , Flavivirus Infections/drug therapy , Humans , Models, Molecular , Viral Proteins/metabolism , Virus ReplicationABSTRACT
Iminosugars that are competitive inhibitors of endoplasmic reticulum (ER) α-glucosidases have been demonstrated to have antiviral activity against a diverse set of viruses. A novel iminosugar, UV-4B, has recently been shown to provide protection against lethal infections with dengue and influenza A (H1N1) viruses in mice. In the current study, the breadth of activity of UV-4B against influenza was examined ex vivo and in vivo. Efficacy of UV-4B against influenza A and B viruses was shown in primary human bronchial epithelial cells, a principal target tissue for influenza. Efficacy of UV-4B against influenza A (H1N1 and H3N2 subtypes) and influenza B was demonstrated using multiple lethal mouse models with readouts including mortality and weight loss. Clinical trials are ongoing to demonstrate safety of UV-4B and future studies to evaluate antiviral activity against influenza in humans are planned.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Antiviral Agents/administration & dosage , Influenza A virus/drug effects , Influenza B virus/drug effects , Orthomyxoviridae Infections/drug therapy , 1-Deoxynojirimycin/administration & dosage , 1-Deoxynojirimycin/pharmacology , Animals , Antiviral Agents/pharmacology , Body Weight , Cells, Cultured , Disease Models, Animal , Epithelial Cells/virology , Humans , Mice , Orthomyxoviridae Infections/pathology , Orthomyxoviridae Infections/virology , Survival Analysis , Treatment OutcomeABSTRACT
The antiviral activity of UV-4 was previously demonstrated against dengue virus serotype 2 (DENV2) in multiple mouse models. Herein, step-wise minimal effective dose and therapeutic window of efficacy studies of UV-4B (UV-4 hydrochloride salt) were conducted in an antibody-dependent enhancement (ADE) mouse model of severe DENV2 infection in AG129 mice lacking types I and II interferon receptors. Significant survival benefit was demonstrated with 10-20 mg/kg of UV-4B administered thrice daily (TID) for seven days with initiation of treatment up to 48 h after infection. UV-4B also reduced infectious virus production in in vitro antiviral activity assays against all four DENV serotypes, including clinical isolates. A set of purified enzyme, in vitro, and in vivo studies demonstrated that inhibition of endoplasmic reticulum (ER) α-glucosidases and not the glycosphingolipid pathway appears to be responsible for the antiviral activity of UV-4B against DENV. Along with a comprehensive safety package, these and previously published data provided support for an Investigational New Drug (IND) filing and Phases 1 and 2 clinical trials for UV-4B with an indication of acute dengue disease.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Antiviral Agents/pharmacology , Dengue Virus/drug effects , Glycoside Hydrolase Inhibitors/pharmacology , Severe Dengue/drug therapy , alpha-Glucosidases/metabolism , 1-Deoxynojirimycin/administration & dosage , 1-Deoxynojirimycin/pharmacology , 1-Deoxynojirimycin/therapeutic use , Animals , Antibodies, Viral/blood , Antibody-Dependent Enhancement/drug effects , Antiviral Agents/administration & dosage , Antiviral Agents/therapeutic use , Cells, Cultured , Chlorocebus aethiops , Clinical Trials as Topic , Disease Models, Animal , Drugs, Investigational , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/enzymology , Glycoside Hydrolase Inhibitors/administration & dosage , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/therapeutic use , Humans , Inhibitory Concentration 50 , Mice , Monocytes/virology , Receptors, Interferon/deficiency , Serogroup , Severe Dengue/virology , Vero CellsABSTRACT
Our lead iminosugar analog called UV-4 or N-(9-methoxynonyl)-1-deoxynojirimycin inhibits activity of endoplasmic reticulum (ER) α-glucosidases I and II and is a potent, host-targeted antiviral candidate. The mechanism of action for the antiviral activity of iminosugars is proposed to be inhibition of ER α-glucosidases leading to misfolding of critical viral glycoproteins. These misfolded glycoproteins would then be incorporated into defective virus particles or targeted for degradation resulting in a reduction of infectious progeny virions. UV-4, and its hydrochloride salt known as UV-4B, is highly potent against dengue virus in vitro and promotes complete survival in a lethal dengue virus mouse model. In the current studies, UV-4 was shown to be highly efficacious via oral gavage against both oseltamivir-sensitive and -resistant influenza A (H1N1) infections in mice even if treatment was initiated as late as 48-72 hours after infection. The minimal effective dose was found to be 80-100 mg/kg when administered orally thrice daily. UV-4 treatment did not affect the development of protective antibody responses after either influenza infection or vaccination. Therefore, UV-4 is a promising candidate for further development as a therapeutic intervention against influenza.
Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Antiviral Agents/pharmacology , Drug Resistance, Viral/drug effects , Influenza A Virus, H1N1 Subtype/drug effects , Oseltamivir/pharmacology , 1-Deoxynojirimycin/adverse effects , 1-Deoxynojirimycin/pharmacology , Animals , Antibodies, Viral/biosynthesis , Antiviral Agents/adverse effects , Female , Influenza A Virus, H1N1 Subtype/immunology , Influenza A Virus, H1N1 Subtype/physiology , Lung/drug effects , Male , Mice , Mice, Inbred BALB C , Safety , Time Factors , Viral Load/drug effectsABSTRACT
Iminosugars are capable of targeting the life cycles of multiple viruses by blocking host endoplasmic reticulum α-glucosidase enzymes that are required for competent replication of a variety of enveloped, glycosylated viruses. Iminosugars as a class are approved for use in humans with diseases such as diabetes and Gaucher's disease, providing evidence for safety of this class of compounds. The in vitro antiviral activity of iminosugars has been described in several publications with a subset of these demonstrating in vivo activity against flaviviruses, herpesviruses, retroviruses and filoviruses. Although there is compelling non-clinical in vivo evidence of antiviral efficacy, the efficacy of iminosugars as antivirals has yet to be demonstrated in humans. In the current study, we report a novel iminosugar, UV-12, which has efficacy against dengue and influenza in mouse models. UV-12 exhibits drug-like properties including oral bioavailability and good safety profile in mice and guinea pigs. UV-12 is an example of an iminosugar with activity against multiple virus families that should be investigated in further safety and efficacy studies and demonstrates potential value of this drug class as antiviral therapeutics.
Subject(s)
Antiviral Agents/therapeutic use , Dengue/drug therapy , Imino Sugars/therapeutic use , Orthomyxoviridae Infections/drug therapy , Animals , Antiviral Agents/pharmacology , Dengue Virus/drug effects , Disease Models, Animal , Female , Guinea Pigs , Imino Sugars/pharmacology , Male , Mice , Microbial Sensitivity Tests , Orthomyxoviridae/drug effects , Treatment OutcomeABSTRACT
In recent years, there has been an increase in the perceived threat of biological agents being used against civilian populations. This has prompted an urgent need for the development and procurement of medical countermeasures (MCMs) against highly pathogenic viruses that can prevent morbidity and mortality from infections caused by these agents. To date, antiviral drug development has been largely focused on clinically prevalent chronic infections due to their commercial viability. This has left a huge gap in the drug development path for acute infections of biodefense importance. In this review, we discuss the antiviral research and development initiatives focusing specifically on poxviruses, filoviruses, and equine encephalitis viruses (EEV). We discuss the benefits and technical challenges in the current development strategies and the hurdles in the licensure path for MCMs against these highly pathogenic viruses under the FDA Animal Rule, and we provide recommendations for the path forward.