HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol: Improved Antiviral Activity in Cells

2010 ◽  
Vol 53 (2) ◽  
pp. 607-615 ◽  
Author(s):  
A.K. Mahalingam ◽  
Linda Axelsson ◽  
Jenny K. Ekegren ◽  
Johan Wannberg ◽  
Jacob Kihlström ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Transition State ◽  
Protease Inhibitors ◽  
Tertiary Alcohol ◽  
Hiv 1 ◽  
In Cells

A series of potent HIV-1 protease inhibitors containing a hydroxyethyl secondary amine transition state isostere: synthesis, enzyme inhibition, and antiviral activity

1992 ◽  
Vol 35 (14) ◽  
pp. 2525-2533 ◽  
Author(s):  
Thomas J. Tucker ◽  
William C. Lumma ◽  
Linda S. Payne ◽  
Jenny M. Wai ◽  
S. Jane De Solms ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Transition State ◽  
Protease Inhibitors ◽  
Enzyme Inhibition ◽  
Secondary Amine ◽  
Hiv 1

scholarly journals Two-Carbon-Elongated HIV-1 Protease Inhibitors with a Tertiary-Alcohol-Containing Transition-State Mimic

2008 ◽  
Vol 51 (8) ◽  
pp. 2586-2586 ◽  
Author(s):  
Xiongyu Wu ◽  
Per Öhrngren ◽  
Jenny K. Ekegren ◽  
Johan Unge ◽  
Torsten Unge ◽  
...  
Keyword(s):  
Transition State ◽  
Protease Inhibitors ◽  
Tertiary Alcohol ◽  
Hiv 1

A New Class of HIV-1 Protease Inhibitors Containing a Tertiary Alcohol in the Transition-State Mimicking Scaffold

2005 ◽  
Vol 48 (25) ◽  
pp. 8098-8102 ◽  
Author(s):  
Jenny K. Ekegren ◽  
Torsten Unge ◽  
Mayada Zreik Safa ◽  
Hans Wallberg ◽  
Bertil Samuelsson ◽  
...  
Keyword(s):  
Transition State ◽  
Protease Inhibitors ◽  
Tertiary Alcohol ◽  
New Class ◽  
Hiv 1

HIV-1 protease inhibitors with a tertiary alcohol containing transition-state mimic and various P2 and P1′ substituents

MedChemComm ◽  
2011 ◽  
Vol 2 (8) ◽  
pp. 701 ◽  
Author(s):  
Per Öhrngren ◽  
Xiongyu Wu ◽  
Magnus Persson ◽  
Jenny K. Ekegren ◽  
Hans Wallberg ◽  
...  
Keyword(s):  
Transition State ◽  
Protease Inhibitors ◽  
Tertiary Alcohol ◽  
Hiv 1

Microwave-Accelerated Synthesis of P1‘-Extended HIV-1 Protease Inhibitors Encompassing a Tertiary Alcohol in the Transition-State Mimicking Scaffold

2006 ◽  
Vol 49 (5) ◽  
pp. 1828-1832 ◽  
Author(s):  
Jenny K. Ekegren ◽  
Nina Ginman ◽  
Åsa Johansson ◽  
Hans Wallberg ◽  
Mats Larhed ◽  
...  
Keyword(s):  
Transition State ◽  
Protease Inhibitors ◽  
Tertiary Alcohol ◽  
Hiv 1

Synthesis of P1′-Functionalized Macrocyclic Transition-State Mimicking HIV-1 Protease Inhibitors Encompassing a Tertiary Alcohol

2014 ◽  
Vol 57 (15) ◽  
pp. 6444-6457 ◽  
Author(s):  
Maria De Rosa ◽  
Johan Unge ◽  
Hitesh V. Motwani ◽  
Åsa Rosenquist ◽  
Lotta Vrang ◽  
...  
Keyword(s):  
Transition State ◽  
Protease Inhibitors ◽  
Tertiary Alcohol ◽  
Hiv 1

Two-Carbon-Elongated HIV-1 Protease Inhibitors with a Tertiary-Alcohol-Containing Transition-State Mimic⊥

2008 ◽  
Vol 51 (4) ◽  
pp. 1053-1057 ◽  
Author(s):  
Xiongyu Wu ◽  
Per Öhrngren ◽  
Jenny K. Ekegren ◽  
Johan Unge ◽  
Torsten Unge ◽  
...  
Keyword(s):  
Transition State ◽  
Protease Inhibitors ◽  
Tertiary Alcohol ◽  
Hiv 1

Variations of the P2 group in HIV-1 protease inhibitors containing a tertiary alcohol in the transition-state mimicking scaffold

2006 ◽  
Vol 4 (16) ◽  
pp. 3040 ◽  
Author(s):  
Jenny K. Ekegren ◽  
Johan Gising ◽  
Hans Wallberg ◽  
Mats Larhed ◽  
Bertil Samuelsson ◽  
...  
Keyword(s):  
Transition State ◽  
Protease Inhibitors ◽  
Tertiary Alcohol ◽  
Hiv 1

scholarly journals Halogen Bond Interactions of Novel HIV-1 Protease Inhibitors (PI) (GRL-001-15 and GRL-003-15) with the Flap of Protease Are Critical for Their Potent Activity against Wild-Type HIV-1 and Multi-PI-Resistant Variants

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Shin-ichiro Hattori ◽  
Hironori Hayashi ◽  
Haydar Bulut ◽  
Kalapala Venkateswara Rao ◽  
Prasanth R. Nyalapatla ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Protease Inhibitors ◽  
Active Site ◽  
Fluorine Atom ◽  
Halogen Bond ◽  
The Novel ◽  
Wild Type ◽  
Flap Region ◽  
Hiv 1

ABSTRACTWe generated two novel nonpeptidic HIV-1 protease inhibitors (PIs), GRL-001-15 and GRL-003-15, which contain unique crown-like tetrahydropyranofuran (Crn-THF) and P2′-cyclopropyl-aminobenzothiazole (Cp-Abt) moieties as P2 and P2′ ligands, respectively. GRL-001-15 and GRL-003-15 havemeta-monofluorophenyl andpara-monofluorophenyl at the P1 site, respectively, exert highly potent activity against wild-type HIV-1 with 50% effective concentrations (EC50s) of 57 and 50 pM, respectively, and have favorable cytotoxicity profiles with 50% cytotoxic concentrations (CC50s) of 38 and 11 μM, respectively. The activity of GRL-001-15 against multi-PI-resistant HIV-1 variants was generally greater than that of GRL-003-15. The EC50of GRL-001-15 against an HIV-1 variant that was highly resistant to multiple PIs, including darunavir (DRV) (HIV-1DRVRP30), was 0.17 nM, and that of GRL-003-15 was 3.3 nM, while DRV was much less active, with an EC50of 216 nM. The emergence of HIV-1 variants resistant to GRL-001-15 and GRL-003-15 was significantly delayed compared to that of variants resistant to selected PIs, including DRV. Structural analyses of wild-type protease (PRWT) complexed with the novel PIs revealed that GRL-001-15’smeta-fluorine atom forms halogen bond interactions (2.9 and 3.0 Å) with Gly49 and Ile50, respectively, of the protease flap region and with Pro81′ (2.7 and 3.2 Å), which is located close to the protease active site, and that two fluorine atoms of GRL-142-13 form multiple halogen bond interactions with Gly49, Ile50, Pro81′, Ile82′, and Arg8′. In contrast, GRL-003-15 forms halogen bond interactions with Pro81′ alone, suggesting that the reduced antiviral activity of GRL-003-15 is due to the loss of the interactions with the flap region.

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