Joseph Markowitz
University of Maryland, Baltimore
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Featured researches published by Joseph Markowitz.
FEBS Letters | 2002
Mi Eun Lee; Joseph Markowitz; Jie-Oh Lee; Hayyoung Lee
Cyclic nucleotide phosphodiesterases (PDEs) regulate physiological processes by degrading intracellular second messengers, adenosine‐3′,5′‐cyclic phosphate or guanosine‐3′,5′‐cyclic phosphate. The first crystal structure of PDE4D catalytic domain and a bound inhibitor, zardaverine, was determined. Zardaverine binds to a highly conserved pocket that includes the catalytic metal binding site. Zardaverine fills only a portion of the active site pocket. More selective PDE4 inhibitors including rolipram, cilomilast and roflumilast have additional functional groups that can utilize the remaining empty space for increased binding energy and selectivity. In the crystal structure, the catalytic domain of PDE4D possesses an extensive dimerization interface containing residues that are highly conserved in PDE1, 3, 4, 8 and 9. Mutations of R358D or D322R among these interface residues prohibit dimerization of the PDE4D catalytic domain in solution.
Current Topics in Medicinal Chemistry | 2005
Joseph Markowitz; Alexander D. MacKerell; Thomas H. Charpentier; David J. Weber
S100B interacts with the p53 protein in a calcium-dependent manner and down-regulates its function as a tumor suppressor. Therefore, inhibiting the S100B-p53 interaction represents a new approach for restoring functional wild-type p53 in cancers with elevated S100B such as found in malignant melanoma. A discussion of the biological rational for targeting S100B and a description of methodologies relevant to the discovery of compounds that inhibit S100B-p53 binding, including computational techniques, structural biology techniques, and cellular assays, is presented.
Mini-reviews in Medicinal Chemistry | 2007
Joseph Markowitz; Alexander D. MacKerell; David J. Weber
Typically, malignant melanoma has wild-type p53, and yet this cancer proliferates. S100B, which binds p53 and is up-regulated in melanoma, down-regulates wild-type p53 tumor suppressor function. Inhibitors of the S100B-p53 interaction were identified using computer aided drug design (CADD) combined with NMR methodologies and represent potentially new chemotherapeutics for melanoma.
Biopolymers | 2014
Amlanjyoti Dhar; Shampa Mallick; Piya Ghosh; Atanu Maiti; Israr Ahmed; Seemana Bhattacharya; Tapashi Mandal; Asit Manna; Koushik Roy; Sandeep Singh; Dipak Kumar Nayak; Paul T. Wilder; Joseph Markowitz; David J. Weber; Mrinal K. Ghosh; Samit Chattopadhyay; Rajdeep Guha; Aditya Konar; Santu Bandyopadhyay; Siddhartha Roy
Protein–protein interactions are part of a large number of signaling networks and potential targets for drug development. However, discovering molecules that can specifically inhibit such interactions is a major challenge. S100B, a calcium‐regulated protein, plays a crucial role in the proliferation of melanoma cells through protein–protein interactions. In this article, we report the design and development of a bidentate conformationally constrained peptide against dimeric S100B based on a natural tight‐binding peptide, TRTK‐12. The helical conformation of the peptide was constrained by the substitution of α‐amino isobutyric acid—an amino acid having high helical propensity—in positions which do not interact with S100B. A branched bidentate version of the peptide was bound to S100B tightly with a dissociation constant of 8 nM. When conjugated to a cell‐penetrating peptide, it caused growth inhibition and rapid apoptosis in melanoma cells. The molecule exerts antiproliferative action through simultaneous inhibition of key growth pathways, including reactivation of wild‐type p53 and inhibition of Akt and STAT3 phosphorylation. The apoptosis induced by the bidentate constrained helix is caused by direct migration of p53 to mitochondria. At moderate intravenous dose, the peptide completely inhibits melanoma growth in a mouse model without any significant observable toxicity. The specificity was shown by lack of ability of a double mutant peptide to cause tumor regression at the same dose level. The methodology described here for direct protein–protein interaction inhibition may be effective for rapid development of inhibitors against relatively weak protein–protein interactions for de novo drug development.
Journal of Biological Chemistry | 2004
Jing Lin; Qingyuan Yang; Zhe Yan; Joseph Markowitz; Paul T. Wilder; David J. Weber
Journal of Molecular Biology | 2005
Nathan T. Wright; Kristen M. Varney; Karen C. Ellis; Joseph Markowitz; Rossitza K. Gitti; Danna B. Zimmer; David J. Weber
Journal of Medicinal Chemistry | 2004
Joseph Markowitz; I-Jen Chen; Rossi Gitti; Donna M. Baldisseri; Yongping Pan; Ryan Udan; Alexander D. MacKerell; David J. Weber
Biochemistry | 2005
Joseph Markowitz; Richard R. Rustandi; Kristen M. Varney; Paul T. Wilder; Ryan Udan; Su Ling Wu; William DeW. Horrocks; David J. Weber
Archive | 2003
David J. Weber; Joseph Markowitz; Alexander D. MacKerell
Archive | 2003
Alexander D. MacKerell; Joseph Markowitz; David J. Weber