Recent FDA approval of HIV protease inhibitors in combination with reverse transcriptase inhibitors has marked a new era of AIDS chemotherapy. Despite these important advances, a number of major limitations have emerged: (i) the presence of a substantial """"""""peptide-like"""""""" character in his protease inhibitors; (ii) higher therapeutic doses and inability to cross the blood-brain barrier; (iii) inadequate supply and expensive synthesis; (iv) the tendency of the virus to become resistant to drugs. The research plan involves the design and synthesis of non-peptidal protease inhibitors with improve resistance profiles.
The specific aims of the proposal are: (a) to design and synthesize novel functionalities that replace peptide binding but mimic the biological model of action based upon X-ray crystal structures of the protein-ligand complexes; (b) to further optimize the lead structures based upon molecular modeling and to further optimize the lead structures based upon molecular modeling and structure-based design strategies to combat drug resistance; (c) to demonstrate the utility of such molecular design through the synthesis of small molecule (550 daltons) non-peptidal HIV protease inhibitors (with subnanomolar potency).

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM053386-04
Application #
2713741
Study Section
AIDS and Related Research Study Section 4 (ARRD)
Project Start
1995-09-01
Project End
2002-08-31
Budget Start
1998-09-01
Budget End
1999-08-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Delino, Nicole S; Aoki, Manabu; Hayashi, Hironori et al. (2018) GRL-079, a Novel HIV-1 Protease Inhibitor, Is Extremely Potent against Multidrug-Resistant HIV-1 Variants and Has a High Genetic Barrier against the Emergence of Resistant Variants. Antimicrob Agents Chemother 62:
Ghosh, Arun K; Sarkar, Anindya; Brindisi, Margherita (2018) The Curtius rearrangement: mechanistic insight and recent applications in natural product syntheses. Org Biomol Chem 16:2006-2027
Ghosh, Arun K; Simpson, Hannah M; Veitschegger, Anne M (2018) Enantioselective total synthesis of decytospolide A and decytospolide B using an Achmatowicz reaction. Org Biomol Chem 16:5979-5986
Wong-Sam, Andres; Wang, Yuan-Fang; Zhang, Ying et al. (2018) Drug Resistance Mutation L76V Alters Nonpolar Interactions at the Flap-Core Interface of HIV-1 Protease. ACS Omega 3:12132-12140
Ghosh, Arun K; Ghosh, Koena; Brindisi, Margherita et al. (2018) Design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors with bicyclic isoxazoline carboxamides as the P3 ligand. Bioorg Med Chem Lett 28:2605-2610
Ghosh, Arun K; R Nyalapatla, Prasanth; Kovela, Satish et al. (2018) Design and Synthesis of Highly Potent HIV-1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure-Activity Studies, Biological and X-ray Structural Analysis. J Med Chem 61:4561-4577
Ghosh, Arun K; Jadhav, Ravindra D; Simpson, Hannah et al. (2018) Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands. Eur J Med Chem 160:171-182
Ghosh, Arun K; Rao, Kalapala Venkateswara; Nyalapatla, Prasanth R et al. (2018) Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants. ChemMedChem 13:803-815
Ghosh, Arun K; Nyalapatla, Prasanth R (2017) Total syntheses of both enantiomers of amphirionin 4: A chemoenzymatic based strategy for functionalized tetrahydrofurans. Tetrahedron 73:1820-1830
Ghosh, Arun K; Sean Fyvie, W; Brindisi, Margherita et al. (2017) Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands. Bioorg Med Chem Lett 27:4925-4931

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