Lois L. Wright

Research Field

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Inhomogeneous translational diffusion of monoclonal antibodies on phospholipid Langmuir-Blodgett films

Carolina Digital Repository (University of North Carolina at Chapel Hill) (1988)

Lois L. Wright Arthur G. Palmer N.L. Thompson

10.17615/xac5-v539

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Citations (3)

Development of Dihydropyridone Indazole Amides as Selective Rho-Kinase Inhibitors

Journal of Medicinal Chemistry (2006)

Krista Goodman Haifeng Cui Sarah E. Dowdell Dimitri E. Gaitanopoulos Robert L. Ivy

Rho kinase (ROCK1) mediates vascular smooth muscle contraction and is a potential target for the treatment of hypertension and related disorders. Indazole amide 3 was identified as a potent and selective ROCK1 inhibitor but possessed poor oral bioavailability. Optimization of this lead resulted in the discovery of a series of dihydropyridones, exemplified by 13, with improved pharmacokinetic parameters relative to the initial lead. Indazole substitution played a critical role in decreasing clearance and improving oral bioavailability.

Indazole

Lead compound

Amide

10.1021/jm0609014

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Citations (149)

Conformational changes induced in herpes simplex virus DNA polymerase upon DNA binding.

Proceedings of the National Academy of Sciences (1993)

Klaus Weißhart Alice A. Kuo George R. Painter Lois L. Wright P A Furman

Herpesvirus DNA polymerases are prototypes for alpha-like DNA polymerases and important targets for antiherpesvirus drugs. We have investigated changes in the catalytic subunit of herpes simplex virus DNA polymerase following DNA binding by using the techniques of endogeneous fluorescence quenching and limited proteolysis. The fluorescence studies revealed a reduction in the rate of quenching by acrylamide in the presence of DNA without changes in the wavelength of the emission peak or in the lifetime of the fluorophore, consistent with the possibility of conformational changes. Strikingly, the proteolysis studies revealed that binding to a variety of natural and synthetic DNA and RNA molecules induced the appearance of a new cleavage site for trypsin near residue 1060 of the protein and increased cleavage by trypsin near the center of the protein. The extent of these cleavages correlated with the affinity of the polymerase for these ligands. These data provide strong evidence that binding to nucleic acid polymers induces substantial localized conformational changes in the polymerase. The locations of enhanced tryptic cleavage near sites implicated in substrate recognition and interaction with a processivity factor suggest that the conformational changes are important for catalysis and processivity of this prototype alpha-like DNA polymerase. Inhibition of these changes may provide a mechanism for antiherpesvirus drugs.

Processivity

DNA clamp

DNA polymerase II

Conformational change

DNA polymerase I

10.1073/pnas.90.3.1028

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Citations (18)

Potent and selective P2–P3 ketoamide inhibitors of cathepsin K with good pharmacokinetic properties via favorable P1′, P1, and/or P3 substitutions

Bioorganic & Medicinal Chemistry Letters (2004)

David G. Barrett John G. Catalano David N. Deaton Anne M. Hassell Stacey T. Long

Cysteine protease