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Dive into the research topics where Wayne H. Miller is active.

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Featured researches published by Wayne H. Miller.


Antimicrobial Agents and Chemotherapy | 2002

Potent and Selective Inhibition of Human Cytomegalovirus Replication by 1263W94, a Benzimidazole l-Riboside with a Unique Mode of Action

Karen K. Biron; Robert J. Harvey; Stanley C. Chamberlain; Steven S. Good; Albert A. Smith; Michelle G. Davis; Christine L. Talarico; Wayne H. Miller; Robert Ferris; Ronna E. Dornsife; Sylvia C. Stanat; John C. Drach; Leroy B. Townsend; George Walter Koszalka

ABSTRACT Benzimidazole nucleosides have been shown to be potent inhibitors of human cytomegalovirus (HCMV) replication in vitro. As part of the exploration of structure-activity relationships within this series, we synthesized the 2-isopropylamino derivative (3322W93) of 1H-β-d-ribofuranoside-2-bromo-5,6-dichlorobenzimidazole (BDCRB) and the biologically unnatural l-sugars corresponding to both compounds. One of the l derivatives, 1H-β-l-ribofuranoside-2-isopropylamino-5,6-dichlorobenzimidazole (1263W94), showed significant antiviral potency in vitro against both laboratory HCMV strains and clinical HCMV isolates, including those resistant to ganciclovir (GCV), foscarnet, and BDCRB. 1263W94 inhibited viral replication in a dose-dependent manner, with a mean 50% inhibitory concentration (IC50) of 0.12 ± 0.01 μM compared to a mean IC50 for GCV of 0.53 ± 0.04 μM, as measured by a multicycle DNA hybridization assay. In a single replication cycle, 1263W94 treatment reduced viral DNA synthesis, as well as overall virus yield. HCMV mutants resistant to 1263W94 were isolated, establishing that the target of 1263W94 was a viral gene product. The resistance mutation was mapped to the UL97 open reading frame. The pUL97 protein kinase was strongly inhibited by 1263W94, with 50% inhibition occurring at 3 nM. Although HCMV DNA synthesis was inhibited by 1263W94, the inhibition was not mediated by the inhibition of viral DNA polymerase. The parent benzimidazole d-riboside BDCRB inhibits viral DNA maturation and processing, whereas 1263W94 does not. The mechanism of the antiviral effect of l-riboside 1263W94 is thus distinct from those of GCV and of BDCRB. In summary, 1263W94 inhibits viral replication by a novel mechanism that is not yet completely understood.


Bioorganic & Medicinal Chemistry Letters | 2009

The use of oxadiazole and triazole substituted naphthyridines as HIV-1 integrase inhibitors. Part 1: Establishing the pharmacophore.

Brian A. Johns; Scott H. Allen; James B. Thompson; Edward P. Garvey; Scott A. Foster; Jerry Jeffrey; Wayne H. Miller

A series of HIV-1 integrase inhibitors containing a novel metal binding motif consisting of the 8-hydroxy-1,6-naphthyridine core and either an oxadiazole or triazole has been identified. The design of the key structural components was based on a two-metal coordination pharmacophore. This report presents initial structure-activity data that shows the new chelation architecture delivers potent inhibition in both enzymatic and antiviral assays.


Antimicrobial Agents and Chemotherapy | 2008

The Naphthyridinone GSK364735 Is a Novel, Potent Human Immunodeficiency Virus Type 1 Integrase Inhibitor and Antiretroviral

Edward P. Garvey; Brian A. Johns; Margaret J. Gartland; Scott A. Foster; Wayne H. Miller; Robert G. Ferris; Richard J. Hazen; Mark R. Underwood; Eric E. Boros; James B. Thompson; Cecilia S. Koble; Scott H. Allen; Lee T. Schaller; Ronald G. Sherrill; Tomokazu Yoshinaga; Masanori Kobayashi; Chiaki Wakasa-Morimoto; Shigeru Miki; Koichiro Nakahara; Takeshi Noshi; Akihiko Sato; Tamio Fujiwara

ABSTRACT The naphthyridinone GSK364735 potently inhibited recombinant human immunodeficiency virus type 1 (HIV-1) integrase in a strand transfer assay (mean 50% inhibitory concentration ± standard deviation, 8 ± 2 nM). As expected based on the structure of the drug, it bound competitively with another two-metal binding inhibitor (Kd [binding constant], 6 ± 4 nM). In a number of different cellular assays, GSK364735 inhibited HIV replication with potency at nanomolar concentrations (e.g., in peripheral blood mononuclear cells and MT-4 cells, 50% effective concentrations were 1.2 ± 0.4 and 5 ± 1 nM, respectively), with selectivity indexes of antiviral activity versus in-assay cytotoxicity of at least 2,200. When human serum was added, the antiviral potency decreased (e.g., a 35-fold decrease in the presence of 100% human serum was calculated by extrapolation from the results of the MT-4 cell assay). In cellular assays, GSK364735 blocked viral DNA integration, with a concomitant increase in two-long-terminal-repeat circles. As expected, this integrase inhibitor was equally active against wild-type viruses and mutant viruses resistant to approved drugs targeting either reverse transcriptase or protease. In contrast, some but not all viruses resistant to other integrase inhibitors were resistant to GSK364735. When virus was passaged in the presence of the inhibitor, we identified resistance mutations within the integrase active site that were the same as or similar to mutations arising in response to other two-metal binding inhibitors. Finally, either additive or synergistic effects were observed when GSK364735 was tested in combination with approved antiretrovirals (i.e., no antagonistic effects were seen). Thus, based on all the data, GSK364735 exerted potent antiviral activity through the inhibition of viral DNA integration by interacting at the two-metal binding site within the catalytic center of HIV integrase.


Bioorganic & Medicinal Chemistry Letters | 2009

1,3,4-Oxadiazole substituted naphthyridines as HIV-1 integrase inhibitors. Part 2: SAR of the C5 position

Brian A. Johns; Scott H. Allen; James B. Thompson; Edward P. Garvey; Scott A. Foster; Jerry Jeffrey; Wayne H. Miller

The use of a 1,3,4-oxadiazole in combination with an 8-hydroxy-1,6-naphthyridine ring system has been shown to deliver potent enzyme and antiviral activity through inhibition of viral DNA integration. This report presents a detailed structure-activity investigation of the C5 position resulting in low nM potency for several analogs with an excellent therapeutic index.


Antimicrobial Agents and Chemotherapy | 2002

Kinetic analysis of wild-type and YMDD mutant hepatitis B virus polymerases and effects of deoxyribonucleotide concentrations on polymerase activity.

Richard K. Gaillard; Jennifer Barnard; Vincent Lopez; Paula Hodges; Eric J. Bourne; Lance C. Johnson; Marchelle I. Allen; Patrick Condreay; Wayne H. Miller; Lynn D. Condreay

ABSTRACT Mutations in the YMDD motif of the hepatitis B virus (HBV) DNA polymerase result in reduced susceptibility of HBV to inhibition by lamivudine, at a cost in replication fitness. The mechanisms underlying the effects of YMDD mutations on replication fitness were investigated using both a cell-based viral replication system and an in vitro enzyme assay to examine wild-type (wt) and YMDD-mutant polymerases. We calculated the affinities of wt and YMDD-mutant polymerases for each natural deoxyribonucleoside triphosphate (dNTP) and determined the intracellular concentrations of each dNTP in HepG2 cells under conditions that support HBV replication. In addition, inhibition constants for lamivudine triphosphate were determined for wt and YMDD-mutant polymerases. Relative to wt HBV polymerase, each of the YMDD-mutant polymerases showed increased apparent Km values for the natural dNTP substrates, indicating decreased affinities for these substrates, as well as increased Ki values for lamivudine triphosphate, indicating decreased affinity for the drug. The effect of the differences in apparent Km values between YMDD-mutant polymerase and wt HBV polymerase could be masked by high levels of dNTP substrates (>20 μM). However, assays using dNTP concentrations equivalent to those measured in HepG2 cells under physiological conditions showed decreased enzymatic activity of YMDD-mutant polymerases relative to wt polymerase. Therefore, the decrease in replication fitness of YMDD-mutant HBV strains results from the lower affinities (increased Km values) of the YMDD-mutant polymerases for the natural dNTP substrates and physiological intracellular concentrations of dNTPs that are limiting for the replication of YMDD-mutant HBV strains.


Biochemical and Biophysical Research Communications | 1979

Adenylate deaminase: potent inhibition by 2'-deoxycoformycin 5'-phosphate.

Carl Frieden; Helen R. Gilbert; Wayne H. Miller; Richard L. Miller

Abstract The nucleotide 2′-deoxycoformycin 5′-phosphate has been enzymatically synthesized from 2′-deoxycoformycin and found to be a potent stoichiometric inhibitor of adenylate deaminase from rabbit muscle. It is shown that the inhibitor binds to the active site and may be considered as a possible transition state analog. The inhibition is time dependent which may reflect an inhibitor induced conformational change.


Bioorganic & Medicinal Chemistry Letters | 2011

Combining symmetry elements results in potent naphthyridinone (NTD) HIV-1 integrase inhibitors

Brian A. Johns; Takashi Kawasuji; Eric E. Boros; James B. Thompson; Edward P. Garvey; Scott A. Foster; Jerry Jeffrey; Wayne H. Miller; Noriyuki Kurose; Kenichi Matsumura; Tamio Fujiwara

A series of naphthyridinone HIV-1 integrase strand-transfer inhibitors have been designed based on a psdeudo-C2 symmetry element present in the two-metal chelation pharmacophore. A combination of two distinct inhibitor binding modes resulted in potent inhibition of the integrase strand-transfer reaction in the low nM range. Effects of aryl and N1 substitutions are disclosed including the impact on protein binding adjusted antiviral activity.


Nucleosides, Nucleotides & Nucleic Acids | 2000

Phosphorylation of ganciclovir phosphonate by cellular GMP kinase determines the stereoselectivity of anti-human cytomegalovirus activity.

Wayne H. Miller; Lilia M. Beauchamp; Eric A. Meade; John E. Reardon; Karen K. Biron; Albert A. Smith; Charles A. Goss; Richard L. Miller

Abstract A racemic mixture of ganciclovir phosphonate was resolved by stereoselective phosphorylation using GMP kinase. The R-enantiomer of ganciclovir phosphonate was active against human cytomegalovirus but the S-enantiomer was less active. We show that enantiomeric selectivity of antiviral activity for ganciclovir phosphonate was conferred by stereoselective phosphorylations by mammalian enzymes, not by stereoslective inhibition of DNA polymerase from human cytomegalovirus.


Advances in Experimental Medicine and Biology | 1986

Purine Salvage Enzymes in Trichomonas Vaginalis

Richard L. Miller; Wayne H. Miller

Trichomonas vaginalis is one of four trichomonad species of protozoal parasites that infect humans. Of these, it is the only species which appears to possess pathogenic strains.1


Pediatric Research | 1985

PURINE SALVAGE ENZYMES IN TRICHOMONAS VAGINALIS: 133

Richard L. Miller; Wayne H. Miller

Trichomonas vaginalis, a pathogenic protozoa, is incapable of de novo purine synthesis and is thus dependent on preformed purines. Unlike other protozoa, T. uaginalis is devoid of purine phosphoribosyltransfer activity but has both purine nucleoside phosphorylase (PNP) and purine nucleoside kinase activity. These enzymes comprise a potential route for the salvage of purines in this organism. Both enzymes have been purified and characterized.The purified PNP (mol. wt. 95,000) catalyzed the synthesis and cleavage of guanosine, adenosine and inosine at maximal velocities (μmol/min/mg) of 590:360:240 and 81:16:390 respectively. Km values ranged from 17-54 μM for these purine nucleosides and 21-25 μM for the purine bases. Initial velocity studies in both the synthetic and cleavage direction indicate a sequential mechanism for this enzyme.As a result of the extreme lability of the nucleoside kinase, only a limited purification was possible. The purified enzyme (mol. wt. 16,000) had a specific activity of 34 nmol of GMP formed/min/mg. It was free of interfering activities and catalyzed the phosphorylation (Km μM/Rel. Vmax) of guanosine (1/100), adenosine (200/111) and inosine (20/67). This enzyme appears to be the only purine ribonucleoside kinase activity in extracts of this organism.The finding that both of these enzymes catalyze reactions involving the common purine nucleosides, guanosine and adenosine, suggests that they may act as a coordinated set of enzyme activities to salvage purines and purine ribonucleosides.

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