Boris Feld - Academia.edu (original) (raw)
Papers by Boris Feld
Bioorganic & Medicinal Chemistry Letters, Sep 1, 2003
Bis-(aryl)thioureas were found to be potent and selective inhibitors of cytomegalovirus (CMV) in ... more Bis-(aryl)thioureas were found to be potent and selective inhibitors of cytomegalovirus (CMV) in cultured HFF cells. Of these, the thiazole analogue 38 was investigated as a potential development candidate.
Antimicrobial Agents and Chemotherapy, Jun 1, 2000
Protein secretion is an essential process for bacterial growth, yet there are few if any antimicr... more Protein secretion is an essential process for bacterial growth, yet there are few if any antimicrobial agents which inhibit secretion. An in vivo, high-throughput screen to detect secretion inhibitors was developed based on the translational autoregulation of one of the central protein components, SecA. The assay makes use of a SecA-LacZ fusion reporter construct in Escherichia coli which is induced when secretion is perturbed. Several compounds, including two natural product extracts, which had the ability to induce the reporter fusion were identified and the MICs of these compounds for Staphylococcus aureus strain MN8 were found to be <128 g/ml. Enzyme-linked immunosorbent assay, Western blotting, and immunoprecipitation techniques were used to analyze the affects of these compounds on protein secretion. Six representative compounds presented here appear to be bona fide secretion inhibitors but were found to have deleterious effects on membranes. It was concluded that, while the method described here for identifying inhibitors of secretion is valid, screens such as this, which are directed against the membrane-bound portion of a pathway, may preferentially identify compounds which affect membrane integrity.
![Research paper thumbnail of Identification of [(Naphthalene-1-carbonyl)-amino]-acetic Acid Derivatives as Nonnucleoside Inhibitors of HCV NS5B RNA Dependent RNA Polymerase](https://attachments.academia-assets.com/111770321/thumbnails/1.jpg)
](ChemInform, Dec 7, 2004
A novel series of HCV NS5B RNA dependent RNA polymerase inhibitors containing a naphthalene carbo... more A novel series of HCV NS5B RNA dependent RNA polymerase inhibitors containing a naphthalene carboxamide scaffold were identified by high throughput screening. Optimization of substituents by parallel synthesis and the iterative design towards understanding structure-activity relationship to improve potency are described. Tetra substituted naphthalene 31 displayed potent activity with IC 50 of 120 nM against HCV NS5B enzyme and was selective over a panel of polymerases.
Analytical Biochemistry, Jul 1, 2007
DNA ligase catalyzes the closure of single-strand nicks in double-stranded DNA that arise during ... more DNA ligase catalyzes the closure of single-strand nicks in double-stranded DNA that arise during replication and recombination. Inhibition of bacterial ligase is expected to cause chromosome degradation and cell death, making it an attractive target for new antibacterials. The prototypical bacterial ligase couples the hydrolysis of NAD(+) to phosphodiester bond formation between an adjacent 3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;OH and 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-terminal phosphate of nicked duplex DNA. The first step is the reversible formation of a ligase-adenylate from the reaction between apoenzyme and NAD(+). Inhibitors that compete with NAD(+) are expected to be bacterial specific because eukaryotic DNA ligases use ATP and differ in the sequence composition of their adenylation domain. We report here a high-throughput assay that measures the adenylation reaction specifically by monitoring ligase-AMP formation via scintillation proximity technologies. Escherichia coli DNA ligase was biotinylated in vivo; after reaction with radiolabeled NAD(+), ligase-[(3)H]AMP could be captured onto the streptavidin-coated surface of the solid scintillant. The method was ideal for high-throughput screening because it required minimal manipulations and generated a robust signal with minimal scatter. Certain adenosine analogs were found to inhibit the adenylation assay and had similar potency of inhibition in a DNA ligation assay.
Virology, Aug 1, 2003
A class of disulfide constrained peptides containing a core motif FPWG was identified from a scre... more A class of disulfide constrained peptides containing a core motif FPWG was identified from a screen of phage displayed library using the HCV RNA-dependent RNA polymerase (NS5B) as a bait. Surface plasmon resonance studies showed that three highly purified synthetic constrained peptides bound to immobilized NS5B with estimated K d values ranging from 30 to 60 M. In addition, these peptides inhibited the NS5B activity in vitro with IC 50 ranging from 6 to 48 M, whereas in contrast they had no inhibitory effect on the enzymatic activities of calf thymus polymerase ␣, human polymerase , RSV polymerase, and HIV reverse transcriptase in vitro. Two peptides demonstrated conformation-dependent inhibition since their synthetic linear versions were not inhibitory in the NS5B assay. A constrained peptide with the minimum core motif FPWG retained selective inhibition of NS5B activity with an IC 50 of 50 M. Alanine scan analyses of a representative constrained peptide, FPWGNTW, indicated that residues F1 and W7 were critical for the inhibitory effect of this peptide, although residues P2 and N5 had some measurable inhibitory effect as well. Further analyses of the mechanism of inhibition indicated that these peptides inhibited the formation of preelongation complexes required for the elongation reaction. However, once the preelongation complex was formed, its activity was refractory to peptide inhibition. Furthermore, the constrained peptide FPWGNTW inhibited de novo initiated RNA synthesis by NS5B from a poly(rC) template. These data indicate that the peptides confer selective inhibition of NS5B activity by binding to the enzyme and perturbing an early step preceding the processive elongation step of RNA synthesis.
Journal of Virology, Feb 1, 2004
A novel small molecule inhibitor of human cytomegalovirus (HCMV) was identified as the result of ... more A novel small molecule inhibitor of human cytomegalovirus (HCMV) was identified as the result of screening a chemical library by using a whole-virus infected-cell assay. Synthetic chemistry efforts yielded the analog designated CFI02, a compound whose potency had been increased about 100-fold over an initial inhibitor. The inhibitory concentration of CFI02 in various assays is in the low nanomolar range. CFI02 is a selective and potent inhibitor of HCMV; it has no activity against other CMVs, alphaherpesviruses, or unrelated viruses. Mechanism-of-action studies indicate that CFI02 acts very early in the replication cycle, inhibiting virion envelope fusion with the cell plasma membrane. Mutants resistant to CFI02 have mutations in the abundant virion envelope glycoprotein B that are sufficient to confer resistance. Taken together, the data suggest that CFI02 inhibits glycoprotein B-mediated HCMV virion fusion. Furthermore, CFI02 inhibits the cell-cell spread of HCMV. This is the first study of a potent and selective small molecule inhibitor of CMV fusion and cell-cell spread.
Bioorganic & Medicinal Chemistry Letters, Aug 1, 2004
The preparation of a-methylbenzyl thioureas and their biological activity against varicella zoste... more The preparation of a-methylbenzyl thioureas and their biological activity against varicella zoster virus is described. Several analogs demonstrated IC 50 s < 0.1 lM and their SAR are discussed. These compounds represent a novel class of potent and selective nonnucleoside inhibitors of varicella zoster virus.
Journal of Virology, Feb 15, 2003
A series of nonnucleoside, N-␣-methylbenzyl-N-arylthiourea analogs were identified which demonstr... more A series of nonnucleoside, N-␣-methylbenzyl-N-arylthiourea analogs were identified which demonstrated selective activity against varicella-zoster virus (VZV) but were inactive against other human herpesviruses, including herpes simplex virus. Representative compounds had potent activity against VZV early-passage clinical isolates and an acyclovir-resistant isolate. Resistant viruses generated against one inhibitor were also resistant to other compounds in the series, suggesting that this group of related small molecules was acting on the same virus-specific target. Sequencing of the VZV ORF54 gene from two independently derived resistant viruses revealed mutations in ORF54 compared to the parental VZV strain Ellen sequence. Recombinant VZV in which the wild-type ORF54 sequence was replaced with the ORF54 gene from either of the resistant viruses became resistant to the series of inhibitor compounds. Treatment of VZV-infected cells with the inhibitor impaired morphogenesis of capsids. Inhibitor-treated cells lacked DNA-containing dense-core capsids in the nucleus, and only incomplete virions were present on the cell surface. These data suggest that the VZV-specific thiourea inhibitor series block virus replication by interfering with the function of the ORF54 protein and/or other proteins that interact with the ORF54 protein.
Journal of Medicinal Chemistry, Nov 19, 2004
A novel series of HCV NS5B RNA-dependent RNA polymerase inhibitors containing a pyrano[3,4-b]indo... more A novel series of HCV NS5B RNA-dependent RNA polymerase inhibitors containing a pyrano[3,4-b]indole scaffold is described leading to the discovery of compound 16, a highly potent and selective inhibitor that is active in the replicon system.
This article cites 31 articles, 12 of which can be accessed free
Bioorganic & Medicinal Chemistry Letters, Jul 1, 2004
Thiazole derivatives R 0260 Thiourea Inhibitors of Herpes Viruses. Part 2. N-Benzyl-N'-arylthiour... more Thiazole derivatives R 0260 Thiourea Inhibitors of Herpes Viruses. Part 2. N-Benzyl-N'-arylthiourea Inhibitors of CMV.-A series of highly potent thiourea inhibitors of CMV with improved stability properties are synthesized and evaluated. Compound (Ic) is the most potent derivative.-(BLOOM*,
This article cites 30 articles, 8 of which can be accessed free at:
L'invention concerne des derives d'indole substitues en 2 et 3, des compositions comprena... more L'invention concerne des derives d'indole substitues en 2 et 3, des compositions comprenant au moins un derive d'indole substitue en 2 et 3, et des procedes d'utilisation desdits derives dans le traitement ou la prevention d'une infection virale ou d'une pathologie liee a un virus chez un patient.
Journal of Medicinal Chemistry, 1998
Bioorganic & Medicinal Chemistry Letters, 2003
Bis-(aryl)thioureas were found to be potent and selective inhibitors of cytomegalovirus (CMV) in ... more Bis-(aryl)thioureas were found to be potent and selective inhibitors of cytomegalovirus (CMV) in cultured HFF cells. Of these, the thiazole analogue 38 was investigated as a potential development candidate.
Antimicrobial Agents and Chemotherapy, 2002
Human respiratory syncytial virus (RSV), a paramyxovirus, is a major cause of acute upper and low... more Human respiratory syncytial virus (RSV), a paramyxovirus, is a major cause of acute upper and lower respiratory tract infections in infants, young children, and adults. RFI-641 is a novel anti-RSV agent with potent in vitro and in vivo activity. RFI-641 is active against both RSV type A and B strains. The viral specificity and the large therapeutic window of RFI-641 (>100-fold) indicate that the antiviral activity of the compound is not due to adverse effects on normal cells. The potent in vitro activity of RFI-641 can be translated to efficacy in vivo: RFI-641 is efficacious when administered prophylactically by the intranasal route in mice, cotton rats, and African green monkeys. RFI-641 is also efficacious when administered therapeutically (24 h postinfection) in the monkey model. Mechanism of action studies indicate that RFI-641 blocks viral F protein-mediated fusion and cell syncytium formation.
The preparation of a-methylbenzyl thioureas and their biological activity against varicella zoste... more The preparation of a-methylbenzyl thioureas and their biological activity against varicella zoster virus is described. Several analogs demonstrated IC 50 s < 0.1 lM and their SAR are discussed. These compounds represent a novel class of potent and selective nonnucleoside inhibitors of varicella zoster virus.
Bioorganic & Medicinal Chemistry Letters, Sep 1, 2003
Bis-(aryl)thioureas were found to be potent and selective inhibitors of cytomegalovirus (CMV) in ... more Bis-(aryl)thioureas were found to be potent and selective inhibitors of cytomegalovirus (CMV) in cultured HFF cells. Of these, the thiazole analogue 38 was investigated as a potential development candidate.
Antimicrobial Agents and Chemotherapy, Jun 1, 2000
Protein secretion is an essential process for bacterial growth, yet there are few if any antimicr... more Protein secretion is an essential process for bacterial growth, yet there are few if any antimicrobial agents which inhibit secretion. An in vivo, high-throughput screen to detect secretion inhibitors was developed based on the translational autoregulation of one of the central protein components, SecA. The assay makes use of a SecA-LacZ fusion reporter construct in Escherichia coli which is induced when secretion is perturbed. Several compounds, including two natural product extracts, which had the ability to induce the reporter fusion were identified and the MICs of these compounds for Staphylococcus aureus strain MN8 were found to be <128 g/ml. Enzyme-linked immunosorbent assay, Western blotting, and immunoprecipitation techniques were used to analyze the affects of these compounds on protein secretion. Six representative compounds presented here appear to be bona fide secretion inhibitors but were found to have deleterious effects on membranes. It was concluded that, while the method described here for identifying inhibitors of secretion is valid, screens such as this, which are directed against the membrane-bound portion of a pathway, may preferentially identify compounds which affect membrane integrity.
ChemInform, Dec 7, 2004
A novel series of HCV NS5B RNA dependent RNA polymerase inhibitors containing a naphthalene carbo... more A novel series of HCV NS5B RNA dependent RNA polymerase inhibitors containing a naphthalene carboxamide scaffold were identified by high throughput screening. Optimization of substituents by parallel synthesis and the iterative design towards understanding structure-activity relationship to improve potency are described. Tetra substituted naphthalene 31 displayed potent activity with IC 50 of 120 nM against HCV NS5B enzyme and was selective over a panel of polymerases.
Analytical Biochemistry, Jul 1, 2007
DNA ligase catalyzes the closure of single-strand nicks in double-stranded DNA that arise during ... more DNA ligase catalyzes the closure of single-strand nicks in double-stranded DNA that arise during replication and recombination. Inhibition of bacterial ligase is expected to cause chromosome degradation and cell death, making it an attractive target for new antibacterials. The prototypical bacterial ligase couples the hydrolysis of NAD(+) to phosphodiester bond formation between an adjacent 3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;OH and 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-terminal phosphate of nicked duplex DNA. The first step is the reversible formation of a ligase-adenylate from the reaction between apoenzyme and NAD(+). Inhibitors that compete with NAD(+) are expected to be bacterial specific because eukaryotic DNA ligases use ATP and differ in the sequence composition of their adenylation domain. We report here a high-throughput assay that measures the adenylation reaction specifically by monitoring ligase-AMP formation via scintillation proximity technologies. Escherichia coli DNA ligase was biotinylated in vivo; after reaction with radiolabeled NAD(+), ligase-[(3)H]AMP could be captured onto the streptavidin-coated surface of the solid scintillant. The method was ideal for high-throughput screening because it required minimal manipulations and generated a robust signal with minimal scatter. Certain adenosine analogs were found to inhibit the adenylation assay and had similar potency of inhibition in a DNA ligation assay.
Virology, Aug 1, 2003
A class of disulfide constrained peptides containing a core motif FPWG was identified from a scre... more A class of disulfide constrained peptides containing a core motif FPWG was identified from a screen of phage displayed library using the HCV RNA-dependent RNA polymerase (NS5B) as a bait. Surface plasmon resonance studies showed that three highly purified synthetic constrained peptides bound to immobilized NS5B with estimated K d values ranging from 30 to 60 M. In addition, these peptides inhibited the NS5B activity in vitro with IC 50 ranging from 6 to 48 M, whereas in contrast they had no inhibitory effect on the enzymatic activities of calf thymus polymerase ␣, human polymerase , RSV polymerase, and HIV reverse transcriptase in vitro. Two peptides demonstrated conformation-dependent inhibition since their synthetic linear versions were not inhibitory in the NS5B assay. A constrained peptide with the minimum core motif FPWG retained selective inhibition of NS5B activity with an IC 50 of 50 M. Alanine scan analyses of a representative constrained peptide, FPWGNTW, indicated that residues F1 and W7 were critical for the inhibitory effect of this peptide, although residues P2 and N5 had some measurable inhibitory effect as well. Further analyses of the mechanism of inhibition indicated that these peptides inhibited the formation of preelongation complexes required for the elongation reaction. However, once the preelongation complex was formed, its activity was refractory to peptide inhibition. Furthermore, the constrained peptide FPWGNTW inhibited de novo initiated RNA synthesis by NS5B from a poly(rC) template. These data indicate that the peptides confer selective inhibition of NS5B activity by binding to the enzyme and perturbing an early step preceding the processive elongation step of RNA synthesis.
Journal of Virology, Feb 1, 2004
A novel small molecule inhibitor of human cytomegalovirus (HCMV) was identified as the result of ... more A novel small molecule inhibitor of human cytomegalovirus (HCMV) was identified as the result of screening a chemical library by using a whole-virus infected-cell assay. Synthetic chemistry efforts yielded the analog designated CFI02, a compound whose potency had been increased about 100-fold over an initial inhibitor. The inhibitory concentration of CFI02 in various assays is in the low nanomolar range. CFI02 is a selective and potent inhibitor of HCMV; it has no activity against other CMVs, alphaherpesviruses, or unrelated viruses. Mechanism-of-action studies indicate that CFI02 acts very early in the replication cycle, inhibiting virion envelope fusion with the cell plasma membrane. Mutants resistant to CFI02 have mutations in the abundant virion envelope glycoprotein B that are sufficient to confer resistance. Taken together, the data suggest that CFI02 inhibits glycoprotein B-mediated HCMV virion fusion. Furthermore, CFI02 inhibits the cell-cell spread of HCMV. This is the first study of a potent and selective small molecule inhibitor of CMV fusion and cell-cell spread.
Bioorganic & Medicinal Chemistry Letters, Aug 1, 2004
The preparation of a-methylbenzyl thioureas and their biological activity against varicella zoste... more The preparation of a-methylbenzyl thioureas and their biological activity against varicella zoster virus is described. Several analogs demonstrated IC 50 s < 0.1 lM and their SAR are discussed. These compounds represent a novel class of potent and selective nonnucleoside inhibitors of varicella zoster virus.
Journal of Virology, Feb 15, 2003
A series of nonnucleoside, N-␣-methylbenzyl-N-arylthiourea analogs were identified which demonstr... more A series of nonnucleoside, N-␣-methylbenzyl-N-arylthiourea analogs were identified which demonstrated selective activity against varicella-zoster virus (VZV) but were inactive against other human herpesviruses, including herpes simplex virus. Representative compounds had potent activity against VZV early-passage clinical isolates and an acyclovir-resistant isolate. Resistant viruses generated against one inhibitor were also resistant to other compounds in the series, suggesting that this group of related small molecules was acting on the same virus-specific target. Sequencing of the VZV ORF54 gene from two independently derived resistant viruses revealed mutations in ORF54 compared to the parental VZV strain Ellen sequence. Recombinant VZV in which the wild-type ORF54 sequence was replaced with the ORF54 gene from either of the resistant viruses became resistant to the series of inhibitor compounds. Treatment of VZV-infected cells with the inhibitor impaired morphogenesis of capsids. Inhibitor-treated cells lacked DNA-containing dense-core capsids in the nucleus, and only incomplete virions were present on the cell surface. These data suggest that the VZV-specific thiourea inhibitor series block virus replication by interfering with the function of the ORF54 protein and/or other proteins that interact with the ORF54 protein.
Journal of Medicinal Chemistry, Nov 19, 2004
A novel series of HCV NS5B RNA-dependent RNA polymerase inhibitors containing a pyrano[3,4-b]indo... more A novel series of HCV NS5B RNA-dependent RNA polymerase inhibitors containing a pyrano[3,4-b]indole scaffold is described leading to the discovery of compound 16, a highly potent and selective inhibitor that is active in the replicon system.
This article cites 31 articles, 12 of which can be accessed free
Bioorganic & Medicinal Chemistry Letters, Jul 1, 2004
Thiazole derivatives R 0260 Thiourea Inhibitors of Herpes Viruses. Part 2. N-Benzyl-N'-arylthiour... more Thiazole derivatives R 0260 Thiourea Inhibitors of Herpes Viruses. Part 2. N-Benzyl-N'-arylthiourea Inhibitors of CMV.-A series of highly potent thiourea inhibitors of CMV with improved stability properties are synthesized and evaluated. Compound (Ic) is the most potent derivative.-(BLOOM*,
This article cites 30 articles, 8 of which can be accessed free at:
L'invention concerne des derives d'indole substitues en 2 et 3, des compositions comprena... more L'invention concerne des derives d'indole substitues en 2 et 3, des compositions comprenant au moins un derive d'indole substitue en 2 et 3, et des procedes d'utilisation desdits derives dans le traitement ou la prevention d'une infection virale ou d'une pathologie liee a un virus chez un patient.
Journal of Medicinal Chemistry, 1998
Bioorganic & Medicinal Chemistry Letters, 2003
Bis-(aryl)thioureas were found to be potent and selective inhibitors of cytomegalovirus (CMV) in ... more Bis-(aryl)thioureas were found to be potent and selective inhibitors of cytomegalovirus (CMV) in cultured HFF cells. Of these, the thiazole analogue 38 was investigated as a potential development candidate.
Antimicrobial Agents and Chemotherapy, 2002
Human respiratory syncytial virus (RSV), a paramyxovirus, is a major cause of acute upper and low... more Human respiratory syncytial virus (RSV), a paramyxovirus, is a major cause of acute upper and lower respiratory tract infections in infants, young children, and adults. RFI-641 is a novel anti-RSV agent with potent in vitro and in vivo activity. RFI-641 is active against both RSV type A and B strains. The viral specificity and the large therapeutic window of RFI-641 (>100-fold) indicate that the antiviral activity of the compound is not due to adverse effects on normal cells. The potent in vitro activity of RFI-641 can be translated to efficacy in vivo: RFI-641 is efficacious when administered prophylactically by the intranasal route in mice, cotton rats, and African green monkeys. RFI-641 is also efficacious when administered therapeutically (24 h postinfection) in the monkey model. Mechanism of action studies indicate that RFI-641 blocks viral F protein-mediated fusion and cell syncytium formation.
The preparation of a-methylbenzyl thioureas and their biological activity against varicella zoste... more The preparation of a-methylbenzyl thioureas and their biological activity against varicella zoster virus is described. Several analogs demonstrated IC 50 s < 0.1 lM and their SAR are discussed. These compounds represent a novel class of potent and selective nonnucleoside inhibitors of varicella zoster virus.