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Your search keyword '"Kerekes, Angela D."' showing total 5 results
Start Over Author "Kerekes, Angela D." Publication Type Magazines
5 results on '"Kerekes, Angela D."'

1. Series of Novel and Highly Potent Cyclic Peptide PCSK9 Inhibitors Derived from an mRNA Display Screen and Optimized via Structure-Based Design

Author

Alleyne, Candice, Amin, Rupesh P., Bhatt, Bhavana, Bianchi, Elisabetta, Blain, J. Craig, Boyer, Nicolas, Branca, Danila, Embrey, Mark W., Ha, Sookhee N., Jette, Kelli, Johns, Douglas G., Kerekes, Angela D., Koeplinger, Kenneth A., LaPlaca, Derek, Li, Nianyu, Murphy, Beth, Orth, Peter, Ricardo, Alonso, Salowe, Scott, Seyb, Kathleen, Shahripour, Aurash, Stringer, Joseph R., Sun, Yili, Tracy, Rodger, Wu, Chengwei, Xiong, Yusheng, Youm, Hyewon, Zokian, Hratch J., and Tucker, Thomas J.

Abstract

Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. In this paper, we describe a series of novel cyclic peptides derived from an mRNA display screen which inhibit the protein–protein interaction between PCSK9 and LDLR. Using a structure-based drug design approach, we were able to modify our original screening lead 2to optimize the potency and metabolic stability and minimize the molecular weight to provide novel bicyclic next-generation PCSK9 inhibitor peptides such as 78. These next-generation peptides serve as a critical foundation for continued exploration of potential oral, once-a-day PCSK9 therapeutics for the treatment of cardiovascular disease.

Published
2020
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3. A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors

Author

Tucker, Thomas J., Embrey, Mark W., Alleyne, Candice, Amin, Rupesh P., Bass, Alan, Bhatt, Bhavana, Bianchi, Elisabetta, Branca, Danila, Bueters, Tjerk, Buist, Nicole, Ha, Sookhee N., Hafey, Mike, He, Huaibing, Higgins, John, Johns, Douglas G., Kerekes, Angela D., Koeplinger, Kenneth A., Kuethe, Jeffrey T., Li, Nianyu, Murphy, BethAnn, Orth, Peter, Salowe, Scott, Shahripour, Aurash, Tracy, Rodger, Wang, Weixun, Wu, Chengwei, Xiong, Yusheng, Zokian, Hratch J., Wood, Harold B., and Walji, Abbas

Abstract

Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. Starting from second-generation lead structures such as 2, we were able to refine these structures to obtain extremely potent bi- and tricyclic PCSK9 inhibitor peptides. Optimized molecules such as 44demonstrated sufficient oral bioavailability to maintain therapeutic levels in rats and cynomolgus monkeys after dosing with an enabled formulation. We demonstrated target engagement and LDL lowering in cynomolgus monkeys essentially identical to those observed with the clinically approved, parenterally dosed antibodies. These molecules represent the first report of highly potent and orally bioavailable macrocyclic peptide PCSK9 inhibitors with overall profiles favorable for potential development as once-daily oral lipid-lowering agents. In this manuscript, we detail the design criteria and multiparameter optimization of this novel series of PCSK9 inhibitors.

Published
2021
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