In collaboration with Professor Ralph Hirschmann we have developed the nitrogen-displaced and carbonyl-displaced pyrrolinone scaffolds were designed to mimic both the hydrogen-bonding pattern and side-chain orientation of the b-sheet/b-strand conformation of peptides.The success of this design led to the development of potent pyrrolinone-based inhibitors of several proteolytic enzymes including HIV-1 protease, Renin, and matrix metalloproteases. More recently, we have extended the utility of the pyrrolinone scaffold by demonstrating that simple structural modifications lead to turned conformations mimicking the peptidal b-turn. Current pyrrolinone research is focused on improving the potency of our HIV-1 protease inhibitors and further development of the pyrrolinones as peptidomimetic scaffolds capable of adopting b-strand, b-turn, and helical conformations.
   

 

Related Publications

 
502   

 

 A. B. smith, A. K. Charnley, H. Harada, J. J. Beiger, L.-D. Cantin, C.S. Kenesky, R. Hirschmann, S. Munshi, D. B. Olsen, M. W. Stahlhut, W. A. Schleif, and L. C. Kuo. Design, Synthesis and Biological Evaluation of Monopyrrolinone-Based HIV-1 Protease Inhibitors Possessing Augmented P2 Side-Chains. Bioorg. Med. Chem. Lett. 2006, 16, 859-863.

 
475   

 

 Smith, Amos B., III; Charnley, Adam K.; Mesaros, Eugen F.; Kikuchi, Osamu; Wang, Wenyong; Benowitz, Andrew; Chu, Chi-Lien; Feng, Jin-Jye; Chen, Kuo-Hsin; Lin, Atsui; Cheng, Fong-Chi; Taylor, Laurie; Hirschmann, Ralph. Design, Synthesis, and Binding Affinities of Pyrrolinone-Based Somatostatin Mimetics. Organic Letters (2005), 7(3), 399-402.

 
444   

 

 Smith, Amos B., III; Cantin, Louis-David; Pasternak, Alexander; Guise-Zawacki, Lisa; Yao, Wenquin; Charnley, Adam K.; Barbosa, Joseph; Sprengeler, Paul A.; Hirschmann, Ralph; Munshi, Sanjeev; Olsen, David B.; Schleif, William A.; Kuo, Lawrence C. Design, Synthesis, and Biological Evaluation of Monopyrrolinone-Based HIV-1 Protease Inhibitors. Journal of Medicinal Chemistry (2003), 46(10), 1831-1844.

 
405   

 

 Smith, Amos B., III; Nittoli, Thomas; Sprengeler, Paul A.; Duan, James J.-W.; Liu, Rui-Qin; Hirschmann, Ralph F. Design, Synthesis, and Evaluation of a Pyrrolinone-Based Matrix Metalloprotease Inhibitor. Organic Letters (2000), 2(24), 3809-3812.

 
402   

 

 Smith, Amos B., III; Wang, Wenyong; Sprengeler, Paul A.; Hirschmann, Ralph. Design, Synthesis, and Solution Structure of a Pyrrolinone-Based b-Turn Peptidomimetic. Journal of the American Chemical Society (2000), 122(44), 11037-11038.

 
399   

 

 Lee, Kon Ho; Olson, Gary L.; Bolin, David R.; Benowitz, Andrew B.; Sprengeler, Paul A.; Smith, Amos B., III; Hirschmann, Ralph F.; Wiley, Don C. The Crystal Structure of a Pyrrolinone-Peptide Hybrid Ligand Bound to the Human Class II MHC Protein HLA-DR1. Journal of the American Chemical Society (2000), 122(35), 8370-8375.

 
397   

 

 Smith, Amos B. ,III; Liu, Hu; Okumura, Hiroyuki; Favor, David A.; Hirschmann, Ralph. Synthesis of Polypyrrolinones on Solid Support. Organic Letters (2000), 2(14), 2041-2044.

 
396   

 

 Smith, Amos B., III; Liu, Hu; Hirschmann, Ralph. A Second-Generation Synthesis of Polypyrrolinone Nonpeptidomimetics: Prelude to the Synthesis of Polypyrrolinones on Solid Support. Organic Letters (2000), 2(14), 2037-2040.

 
379   

 

 Smith, Amos B., III; Benowitz, Andrew B.; Sprengeler, Paul A.; Barbosa, Joseph; Guzman, Mark C.; Hirschmann, Ralph; Schweiger, Edwin J.; Bolin, David R.; Nagy, Zoltan; Campbell, Robert M.; Cox, Donald C.; Olson, Gary L. Design and Synthesis of a Competent Pyrrolinone-Peptide Hybrid Ligand for the Class II Major Histocompatibility Complex Protein HLA-DR1. Journal of the American Chemical Society (1999), 121(40), 9286-9298.

 
368   

 

 Smith, Amos B., III; Favor, David A.; Sprengeler, Paul A.; Guzman, Mark C.; Carroll, Patrick J.; Furst, George T.; Hirschmann, Ralph. Molecular modeling, synthesis, and structures of N-methylated 3,5-linked pyrrolin-4-ones toward the creation of a privileged nonpeptide scaffold. Bioorganic & Medicinal Chemistry (1999), 7(1), 9-22.

 
365   

 

 Smith, Amos B. ,III; Benowitz, Andrew B.; Guzman, Mark C.; Sprengeler, Paul A.; Hirschmann, Ralph; Schweiger, Edwin J.; Bolin, David R.; Nagy, Zoltan; Campbell, Robert M.; Cox, Donald C.; Olson, Gary L. Design, synthesis, and evaluation of a pyrrolinone-peptide hybrid ligand for the class II MHC protein HLA-DR1. Journal of the American Chemical Society (1998), 120(48), 12704-12705.

 
356   

 

 Sudoh, Masao; Pauletti, Giovanni M.; Yao, Wenqing; Moser, William; Yokoyama, Akihisa; Pasternak, Alexander; Sprengeler, Paul A.; Smith, Amos B., III; Hirschmann, Ralph; Borchardt, Ronald T. Transport characteristics of peptidomimetics. Effect of the pyrrolinone bioisostere on transport across Caco-2 cell monolayers. Pharmaceutical Research (1998), 15(5), 719-725.

 
341   

 

 Smith, Amos B., III; Hirschmann, Ralph; Pasternak, Alexander; Yao, Wenquing; Sprengeler, Paul A.; Holloway, M. Katharine; Kuo, Lawrence C.; Chen, Zhongguo; Darke, Paul L.; Schleif, William A. An Orally Bioavailable Pyrrolinone Inhibitor of HIV-1 Protease: Computational Analysis and X-ray Crystal Structure of the Enzyme Complex. Journal of Medicinal Chemistry (1997), 40(16), 2440-2444.

 
324   

 

 Smith, Amos B., III; Knight, Steven D.; Sprengeler, Paul A.; Hirschmann, Ralph. The design and synthesis of 2,5-linked pyrrolinones. A potential non-peptide peptidomimetic scaffold. Bioorganic & Medicinal Chemistry (1996), 4(7), 1021-1034.

 
311   

 

 Smith, Amos B,. III; Hirschmann, Ralph; Pasternak, Alexander; Guzman, Mark C.; Yokoyama, Akihisa; Sprengeler, Paul A.; Darke, Paul L.; Emini, Emilio A.; Schleif, William A. Pyrrolinone-Based HIV Protease Inhibitors. Design, Synthesis, and Antiviral Activity: Evidence for Improved Transport. Journal of the American Chemical Society (1995), 117(45), 11113-23.

 
296   

 

 Smith, III, Amos B.; Akaishi, Ryouichi; Jones, David R.; Keenan, Terence P.; Guzman, Mark C.; Holcomb, Ryan C.; Sprengeler, Paul A.; Wood, John L.; Hirschmann, Ralph; Holloway, M. Katharine. Design and synthesis of nonpeptide peptidomimetic inhibitors of renin. Biopolymers (1995), 37(1), 29-53.

 
286   

 

 Smith, Amos B., III; Guzman, Mark C.; Sprengeler, Paul A.; Keenan, Terence P.; Holcomb, Ryan C.; Wood, John L.; Carroll, Patrick J.; Hirschmann, Ralph. De Novo Design, Synthesis, and X-ray Crystal Structures of Pyrrolinone-Based b-Strand Peptidomimetics. Journal of the American Chemical Society (1994), 116 (22), 9947-62.

 
268   

 

 Smith, Amos B., III; Hirschmann, Ralph; Pasternak, Alexander; Akaishi, Ryouichi; Guzman, Mark C.; Jones, David R.; Keenan, Terence P.; Sprengeler, Paul A.; Darke, Paul L.; et al. Design and synthesis of peptidomimetic inhibitors of HIV-1 protease and renin. Evidence for improved transport. Journal of Medicinal Chemistry (1994), 37 (2), 215-18.

 
234   

 

 Smith, Amos B., III; Keenan, Terence P.; Holcomb, Ryan C.; Sprengeler, Paul A.; Guzman, Mark C.; Wood, John L.; Carroll, Patrick J.; Hirschmann, Ralph. Design, synthesis, and crystal structure of a pyrrolinone-based peptidomimetic possessing the conformation of a b-strand: potential application to the design of novel inhibitors of proteolytic enzymes. Journal of the American Chemical Society (1992), 114 (26), 10672-4.

 

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