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Dive into the research topics where Dwight D. Weller is active.

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Featured researches published by Dwight D. Weller.


Antimicrobial Agents and Chemotherapy | 2009

Chemical modifications of antisense morpholino oligomers enhance their efficacy against Ebola virus infection.

Dana L. Swenson; Kelly L. Warfield; Travis K. Warren; Candace Lovejoy; Jed N. Hassinger; Gordon Ruthel; Robert E. Blouch; Hong M. Moulton; Dwight D. Weller; Patrick L. Iversen; Sina Bavari

ABSTRACT Phosphorodiamidate morpholino oligomers (PMOs) are uncharged nucleic acid-like molecules designed to inactivate the expression of specific genes via the antisense-based steric hindrance of mRNA translation. PMOs have been successful at knocking out viral gene expression and replication in the case of acute viral infections in animal models and have been well tolerated in human clinical trials. We propose that antisense PMOs represent a promising class of therapeutic agents that may be useful for combating filoviral infections. We have previously shown that mice treated with a PMO whose sequence is complementary to a region spanning the start codon of VP24 mRNA were protected against lethal Ebola virus challenge. In the present study, we report on the abilities of two additional VP24-specific PMOs to reduce the cell-free translation of a VP24 reporter, to inhibit the in vitro replication of Ebola virus, and to protect mice against lethal challenge when the PMOs are delivered prior to infection. Additionally, structure-activity relationship evaluations were conducted to assess the enhancement of antiviral efficacy associated with PMO chemical modifications that included conjugation with peptides of various lengths and compositions, positioning of conjugated peptides to either the 5′ or the 3′ terminus, and the conferring of charge modifications by the addition of piperazine moieties. Conjugation with arginine-rich peptides greatly enhanced the antiviral efficacy of VP24-specific PMOs in infected cells and mice during lethal Ebola virus challenge.


Antimicrobial Agents and Chemotherapy | 2006

Gene-Specific Effects of Antisense Phosphorodiamidate Morpholino Oligomer-Peptide Conjugates on Escherichia coli and Salmonella enterica Serovar Typhimurium in Pure Culture and in Tissue Culture

Lucas D. Tilley; Orion S. Hine; Jill A. Kellogg; Jed N. Hassinger; Dwight D. Weller; Patrick L. Iversen; Bruce L. Geller

ABSTRACT The objective was to improve efficacy of antisense phosphorodiamidate morpholino oligomers (PMOs) by improving their uptake into bacterial cells. Four different bacterium-permeating peptides, RFFRFFRFFXB, RTRTRFLRRTXB, RXXRXXRXXB, and KFFKFFKFFKXB (X is 6-aminohexanoic acid and B isβ -alanine), were separately coupled to two different PMOs that are complementary to regions near the start codons of a luciferase reporter gene (luc) and a gene required for viability (acpP). Luc peptide-PMOs targeted to luc inhibited luciferase activity 23 to 80% in growing cultures of Escherichia coli. In cell-free translation reactions, Luc RTRTRFLRRTXB-PMO inhibited luciferase synthesis significantly more than the other Luc peptide-PMOs or the Luc PMO not coupled to peptide. AcpP peptide-PMOs targeted to acpP inhibited growth of E. coli or Salmonella enterica serovar Typhimurium to various extents, depending on the strain. The concentrations of AcpP RFFRFFRFFXB-PMO, AcpP RTRTRFLRRTXB-PMO, AcpP KFFKFFKFFKXB-PMO, and ampicillin that reduced CFU/ml by 50% after 8 h of growth (50% inhibitory concentration [IC50]) were 3.6, 10.8, 9.5, and 7.5μ M, respectively, in E. coli W3110. Sequence-specific effects of AcpP peptide-PMOs were shown by rescuing growth of a merodiploid strain that expressed acpP with silent mutations in the region targeted by AcpP peptide-PMO. In Caco-2 cultures infected with enteropathogenic E. coli (EPEC), 10 μM AcpP RTRTRFLRRTXB-PMO or AcpP RFFRFFRFFXB-PMO essentially cleared the infection. The IC50 of either AcpP RTRTRFLRRTXB-PMO or AcpP RFFRFFRFFXB-PMO in EPEC-infected Caco-2 culture was 3 μM. In summary, RFFRFFRFFXB, RTRTRFLRRTXB, or KFFKFFKFFXB, when covalently bonded to PMO, significantly increased inhibition of expression of targeted genes compared to PMOs without attached peptide.


Methods in Enzymology | 2000

Evaluation of antisense mechanisms of action.

Chandramallika Ghosh; David A. Stein; Dwight D. Weller; Patrick L. Iversen

Publisher Summary Antisense inhibition of gene expression may provide for highly effective therapeutic applications as well as powerful tools in the exploration of gene function. This promise is currently facilitated by an ever-widening spectrum of oligonucleotide chemistries. However, key mechanistic questions need to be addressed for each chemistry, for each target gene, and for each oligonucleotide sequence. Further, prevailing questions regarding appropriate negative control oligonucleotides can best be addressed when a definitive mechanism of action is known. This chapter discusses the idea that evaluation of the inhibition of gene expression can be defined in quantitative terms consistent with inhibitors of enzymatic reactions and/or receptor antagonists. Hence, the V max , K m (alternatively B max , K d ), and K i terms may be defined, and the comparison of oligonucleotide chemistries as well as comparisons with alternative methods of inhibition may be described. The site of oligonucleotide action within the cell may define different mechanisms such as interaction with transcription factors, formation of triple helix with DNA, interference with pre-mRNA splicing, or invasion of a DNA duplex. These mechanisms do not involve hybridization with mature mRNA. This mechanistic and quantitative evaluation of ohgonucleotide RNA duplexes should allow comparisons from in vitro to cell culture and to in vivo applications. The potential for contributions by nonspecific or aptameric effects such as those defined for phosphorothioate oligonucleotides, including oligonucleotide interactions with extracellular and cellular proteins, and short heteroduplex recognition of RNase H, can be observed. Finally, the quantitative agreement or potential disagreement with the rules of base pairing, including base mismatches described by Aboul-ela et al., can be evaluated experimentally.


Nucleosides, Nucleotides & Nucleic Acids | 1997

Antisense Properties of Morpholino Oligomers

James E. Summerton; Dwight D. Weller

Abstract Morpholino oligomers are third generation antisense agents designed to be cost effective, water soluble and resistant to nuclease attack. They show high potency and sequence specificity and follow predictable targeting rules when used in antisense applications in cell culture.


Nucleosides, Nucleotides & Nucleic Acids | 1997

Molecular Engine for Transporting Drugs Across Cell Membranes

James E. Summerton; Dwight D. Weller

Abstract A molecular engine has been developed from first principles to transport drugs from endosomes to the cytosol of cells. The engine is powered by the pH differential across the endosomal membrane, does not disrupt the endosomal membrane, and is disassembled into innocuous components after carrying out its transport function.


Archive | 1989

Uncharged morpholino-based polymers having achiral intersubunit linkages

James E. Summerton; Dwight D. Weller


Antisense & Nucleic Acid Drug Development | 1997

Morpholino antisense oligomers: design, preparation, and properties.

James E. Summerton; Dwight D. Weller


Archive | 1989

Alpha-morpholino ribonucleoside derivatives and polymers thereof

James E. Summerton; Dwight D. Weller; Eugene P. Stirchak


Archive | 1991

Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages

James E. Summerton; Dwight D. Weller


Archive | 1995

Morpholino-subunit combinatorial library and method

James E. Summerton; Dwight D. Weller

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Muralimohan T. Reddy

Beth Israel Deaconess Medical Center

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