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1.
Antiviral Res ; 208: 105444, 2022 12.
Article in English | MEDLINE | ID: mdl-36243175

ABSTRACT

Infections by pathogenic New World mammarenaviruses (NWM)s, including Junín virus (JUNV), can result in a severe life-threatening viral hemorrhagic fever syndrome. In the absence of FDA-licensed vaccines or antivirals, these viruses are considered high priority pathogens. The mammarenavirus envelope glycoprotein complex (GPC) mediates pH-dependent fusion between viral and cellular membranes, which is essential to viral entry and may be vulnerable to small-molecule inhibitors that disrupt this process. ARN-75039 is a potent fusion inhibitor of a broad spectrum of pseudotyped and native mammarenaviruses in cell culture and Tacaribe virus infection in mice. In the present study, we evaluated ARN-75039 against pathogenic JUNV in the rigorous guinea pig infection model. The compound was well-tolerated and had favorable pharmacokinetics supporting once-per-day oral dosing in guinea pigs. Importantly, significant protection against JUNV challenge was observed even when ARN-75039 was withheld until 6 days after the viral challenge when clinical signs of disease are starting to develop. We also show that ARN-75039 combination treatment with favipiravir, a viral polymerase inhibitor, results in synergistic activity in vitro and improves survival outcomes in JUNV-challenged guinea pigs. Our findings support the continued development of ARN-75039 as an attractive therapeutic candidate for treating mammarenaviral hemorrhagic fevers, including those associated with NWM infection.


Subject(s)
Arenaviridae , Hemorrhagic Fever, American , Hemorrhagic Fevers, Viral , Junin virus , Guinea Pigs , Mice , Animals , Hemorrhagic Fever, American/drug therapy , Pyrazines/pharmacology , Pyrazines/therapeutic use , Amides/pharmacology , Amides/therapeutic use , Anti-Retroviral Agents/pharmacology
2.
Antiviral Res ; 193: 105125, 2021 09.
Article in English | MEDLINE | ID: mdl-34197863

ABSTRACT

Several arenaviruses, including Lassa and Lujo viruses in Africa and five New World arenavirus (NWA) species in the Americas, cause life-threatening viral hemorrhagic fevers. In the absence of licensed antiviral therapies, these viruses pose a significant public health risk. The envelope glycoprotein complex (GPC) mediates arenavirus entry through a pH-dependent fusion of the viral and host endosomal membranes. It thus is recognized as a viable target for small-molecule fusion inhibitors. Here, we report on the antiviral activity and pre-clinical development of the novel broad-spectrum arenavirus fusion inhibitors, ARN-75039 and ARN-75041. In Tacaribe virus (TCRV) pseudotyped and native virus assays, the ARN compounds were active in the low to sub-nanomolar range with selectivity indices exceeding 1000. Pharmacokinetic analysis of the orally administered compounds revealed an extended half-life in mice supporting once-daily dosing, and the compounds were well tolerated at the highest tested dose of 100 mg/kg. In a proof-of-concept prophylactic efficacy study, doses of 10 and 35 mg/kg of either compound dramatically improved survival outcome and potently inhibited TCRV replication in serum and various tissues. Additionally, in contrast to surviving mice that received ribavirin or placebo, animals treated with ARN-75039 or ARN-75041 were cured of TCRV infection. In a follow-up study with ARN-75039, impressive therapeutic efficacy was demonstrated under conditions where treatment was withheld until after the onset of disease. Taken together, the data strongly support the continued development of ARN-75039 as a candidate therapeutic for the treatment of severe arenaviral diseases.


Subject(s)
Antiviral Agents/pharmacology , Arenaviridae Infections/drug therapy , Arenaviruses, New World/drug effects , Membrane Fusion/drug effects , Small Molecule Libraries/pharmacology , Administration, Oral , Animals , Antiviral Agents/pharmacokinetics , Chlorocebus aethiops , Male , Mice , Ribavirin/pharmacology , Small Molecule Libraries/pharmacokinetics , Vero Cells , Viral Envelope Proteins/chemistry , Viral Envelope Proteins/metabolism , Virus Internalization/drug effects
3.
Bioorg Med Chem Lett ; 41: 127983, 2021 06 01.
Article in English | MEDLINE | ID: mdl-33965007

ABSTRACT

We identified and explored the structure-activity relationship (SAR) of a novel heterocyclic chemical series of arenavirus cell entry inhibitors. Optimized lead compounds, including diphenyl-substituted imidazo[1,2-a]pyridines, benzimidazoles, and benzotriazoles exhibited low to sub-nanomolar potency against both pseudotyped and infectious Old and New World arenaviruses, attractive metabolic stability in human and most nonhuman liver microsomes as well as a lack of hERG K + channel or CYP enzyme inhibition. Moreover, the straightforward synthesis of several lead compounds (e.g., the simple high yield 3-step synthesis of imidazo[1,2-a]pyridine 37) could provide a cost-effective broad-spectrum arenavirus therapeutic that may help to minimize the cost-prohibitive burdens associated with treatments for emerging viruses in economically challenged geographical settings.


Subject(s)
Antiviral Agents/pharmacology , Arenavirus/drug effects , Drug Discovery , Heterocyclic Compounds/pharmacology , Viral Envelope Proteins/antagonists & inhibitors , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Arenavirus/metabolism , Dose-Response Relationship, Drug , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Humans , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Viral Envelope Proteins/metabolism
4.
ACS Med Chem Lett ; 11(6): 1160-1167, 2020 Jun 11.
Article in English | MEDLINE | ID: mdl-32550996

ABSTRACT

We identified and explored the structure-activity-relationship (SAR) of an adamantane carboxamide chemical series of Ebola virus (EBOV) inhibitors. Selected analogs exhibited half-maximal inhibitory concentrations (EC50 values) of ∼10-15 nM in vesicular stomatitis virus (VSV) pseudotyped EBOV (pEBOV) infectivity assays, low hundred nanomolar EC50 activity against wild type EBOV, aqueous solubility >20 mg/mL, and attractive metabolic stability in human and nonhuman liver microsomes. X-ray cocrystallographic characterizations of a lead compound with the EBOV glycoprotein (GP) established the EBOV GP as a target for direct compound inhibitory activity and further provided relevant structural models that may assist in identifying optimized therapeutic candidates.

5.
Bioorg Med Chem Lett ; 29(22): 126620, 2019 11 15.
Article in English | MEDLINE | ID: mdl-31537423

ABSTRACT

Old World (Africa) and New World (South America) arenaviruses are associated with human hemorrhagic fevers. Efforts to develop small molecule therapeutics have yielded several chemical series including the 4-acyl-1,6-dialkylpiperazin-2-ones. Herein, we describe an extensive exploration of this chemotype. In initial Phase I studies, R1 and R4 scanning libraries were assayed to identify potent substituents against Old World (Lassa) virus. In subsequent Phase II studies, R6 substituents and iterative R1, R4 and R6 substituent combinations were evaluated to obtain compounds with improved Lassa and New World (Machupo, Junin, and Tacaribe) arenavirus inhibitory activity, in vitro human liver microsome metabolic stability and aqueous solubility.


Subject(s)
Antiviral Agents/pharmacology , Arenavirus/drug effects , Piperazines/pharmacology , Viral Envelope Proteins/antagonists & inhibitors , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Arenavirus/metabolism , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Piperazines/chemical synthesis , Piperazines/chemistry , Structure-Activity Relationship , Viral Envelope Proteins/metabolism
6.
Sci Rep ; 4: 5944, 2014 Aug 04.
Article in English | MEDLINE | ID: mdl-25089892

ABSTRACT

Influenza A viruses cause the respiratory illness influenza, which can be mild to fatal depending on the strain and host immune response. The flu polymerase acidic (PA), polymerase basic 1 (PB1), and polymerase basic 2 (PB2) proteins comprise the RNA-dependent RNA polymerase complex responsible for viral genome replication. The first crystal structures of the C-terminal domain of PA (PA-CTD) in the absence of PB1-derived peptides show a number of structural changes relative to the previously reported PB1-peptide bound structures. The human A/WSN/1933 (H1N1) and avian A/Anhui1/2013 (H7N9) strain PA-CTD proteins exhibit the same global topology as other strains in the absence of PB1, but differ extensively in the PB1 binding pocket including a widening of the binding groove and the unfolding of a ß-turn. Both PA-CTD proteins exhibited a significant increase in thermal stability in the presence of either a PB1-derived peptide or a previously reported inhibitor in differential scanning fluorimetry assays. These structural changes demonstrate plasticity in the PA-PB1 binding interface which may be exploited in the development of novel therapeutics.


Subject(s)
Influenza A Virus, H1N1 Subtype/chemistry , Influenza A Virus, H7N9 Subtype/chemistry , RNA-Dependent RNA Polymerase/chemistry , Viral Proteins/chemistry , Amino Acid Sequence , Binding Sites , Crystallography, X-Ray , Enzyme Stability , Escherichia coli/genetics , Escherichia coli/metabolism , Gene Expression , Influenza A Virus, H1N1 Subtype/enzymology , Influenza A Virus, H7N9 Subtype/enzymology , Models, Molecular , Molecular Sequence Data , Protein Binding , Protein Structure, Secondary , Protein Structure, Tertiary , RNA-Dependent RNA Polymerase/genetics , RNA-Dependent RNA Polymerase/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Viral Proteins/genetics , Viral Proteins/metabolism , Virus Replication/physiology
7.
J Med Chem ; 55(2): 725-34, 2012 Jan 26.
Article in English | MEDLINE | ID: mdl-22221201

ABSTRACT

In acute myelogenous leukemia (AML), the FLT3 receptor tyrosine kinase (RTK) is highly expressed with 30% of patients expressing a mutated, constitutively active form of this protein. To inhibit this receptor, VX-322 was developed and found to be very potent against both the FLT3 and c-KIT RTKs with enzyme K(i) values of <1 nM and a cellular IC(50) between 1 and 5 nM. It was efficacious in a FLT3-ITD dependent myeloproliferative mouse model, doubling survival compared to other FLT3 inhibitors, with 25% of the mice cured. Upon treatment of primary AML patient blast cells, the dual inhibition of FLT3 and c-KIT was superior to inhibitors targeting a single RTK. Thus, this compound may represent an improved pharmacologic and selectivity profile that could be effective in the treatment of AML.


Subject(s)
Antineoplastic Agents/pharmacology , Leukemia, Myeloid, Acute/drug therapy , Morpholines/pharmacology , Proto-Oncogene Proteins c-kit/antagonists & inhibitors , Triazoles/pharmacology , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Apoptosis/drug effects , Cell Survival/drug effects , Humans , Male , Mice , Mice, Inbred BALB C , Neoplasm Transplantation , Serum , Tumor Cells, Cultured
8.
J Med Chem ; 54(20): 7184-92, 2011 Oct 27.
Article in English | MEDLINE | ID: mdl-21970471

ABSTRACT

A high-throughput screen of our compound archive revealed a novel class of dual FMS-like tyrosine kinase 3 (FLT3)/c-KIT inhibitors. With the help of molecular modeling, this class was rapidly optimized for both potency against FLT3 and FLT3/c-KIT and excellent potency in cell-based assays, leading to dose-dependent cell death in acute myelogenous leukemia (AML) patient blast samples. Ultimately, the AML patient blast data defined the preferred target profile as we designed and evaluated a set of FLT3 selective and FLT3/c-KIT dual molecules. Further optimization for pharmacokinetic properties resulted in the selection of the dual FLT3/c-KIT inhibitor, N(3)-(4-(trans-4-morpholinocyclohexyl)phenyl)-1-(pyridin-2-yl)-1H-1,2,4-triazole-3,5-diamine, VX-322 (compound 37), to move forward to preclinical evaluation.


Subject(s)
Antineoplastic Agents/chemical synthesis , Leukemia, Myeloid, Acute/pathology , Morpholines/chemical synthesis , Proto-Oncogene Proteins c-kit/antagonists & inhibitors , Triazoles/chemical synthesis , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Design , Drug Screening Assays, Antitumor , Humans , Hydrogen Bonding , Injections, Intravenous , Leukemia, Myeloid, Acute/drug therapy , Macaca fascicularis , Mice , Mice, Inbred BALB C , Models, Molecular , Morpholines/pharmacokinetics , Morpholines/pharmacology , Protein Binding , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Triazoles/pharmacokinetics , Triazoles/pharmacology
9.
J Immunol ; 175(4): 2630-4, 2005 Aug 15.
Article in English | MEDLINE | ID: mdl-16081838

ABSTRACT

Familial cold autoinflammatory syndrome (FCAS) and the related autoinflammatory disorders, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease, are characterized by mutations in the CIAS1 gene that encodes cryopyrin, an adaptor protein involved in activation of IL-converting enzyme/caspase-1. Mutations in cryopyrin are hypothesized to result in abnormal secretion of caspase-1-dependent proinflammatory cytokines, IL-1beta and IL-18. In this study, we examined cytokine secretion in PBMCs from FCAS patients and found a marked hyperresponsiveness of both IL-1beta and IL-18 secretion to LPS stimulation, but no evidence of increased basal secretion of these cytokines, or alterations in basal or stimulated pro-IL-1beta levels. VX-765, an orally active IL-converting enzyme/caspase-1 inhibitor, blocked IL-1beta secretion with equal potency in LPS-stimulated cells from FCAS and control subjects. These results further link mutations in cryopyrin with abnormal caspase-1 activation, and support the clinical testing of caspase-1 inhibitors such as VX-765 in autoinflammatory disorders.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Autoimmune Diseases/immunology , Caspase Inhibitors , Cold Temperature/adverse effects , Cysteine Proteinase Inhibitors/pharmacology , Hypersensitivity/prevention & control , Monocytes/pathology , Adult , Aged , Aged, 80 and over , Autoimmune Diseases/enzymology , Autoimmune Diseases/genetics , Carrier Proteins/genetics , Carrier Proteins/physiology , Caspase 1/biosynthesis , Caspase 1/physiology , Cytokines/metabolism , Drug Evaluation, Preclinical , Female , Humans , Hypersensitivity/enzymology , Hypersensitivity/genetics , Hypersensitivity/immunology , Inflammation/enzymology , Inflammation/genetics , Inflammation/prevention & control , Interleukin-1/antagonists & inhibitors , Interleukin-1/biosynthesis , Interleukin-1/metabolism , Lipopolysaccharides/pharmacology , Male , Middle Aged , Monocytes/enzymology , Monocytes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein , Prodrugs/pharmacology , Protein Precursors/biosynthesis , Syndrome
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