title: GRL-0519, a novel oxatricyclic ligand-containing nonpeptidic HIV-1 protease inhibitor (PI), potently suppresses replication of a wide spectrum of multi-PI-resistant HIV-1 variants in vitro.
abstract: We report that GRL-0519, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing tris-tetrahydrofuranylurethane (tris-THF) and a sulfonamide isostere, is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC50], 0.0005 to 0.0007 μM) with minimal cytotoxicity (50% cytotoxic concentration [CC50], 44.6 μM). GRL-0519 blocked the infectivity and replication of HIV-1NL4-3 variants selected by up to a 5 μM concentration of ritonavir, lopinavir, or atazanavir (EC50, 0.0028 to 0.0033 μM). GRL-0519 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who no longer responded to existing antiviral regimens after long-term antiretroviral therapy, highly darunavir (DRV)-resistant variants, and HIV-2ROD. The development of resistance against GRL-0519 was substantially delayed compared to other PIs, including amprenavir (APV) and DRV. The effects of nonspecific binding of human serum proteins on GRL-0519's antiviral activity were insignificant. Our analysis of the crystal structures of GRL-0519 (3OK9) and DRV (2IEN) with protease suggested that the tris-THF moiety, compared to the bis-THF moiety present in DRV, has greater water-mediated polar interactions with key active-site residues of protease and that the tris-THF moiety and paramethoxy group effectively fill the S2 and S2' binding pockets, respectively, of the protease. The present data demonstrate that GRL-0519 has highly favorable features as a potential therapeutic agent for treating patients infected with wild-type and/or multi-PI-resistant variants and that the tris-THF moiety is critical for strong binding of GRL-0519 to the HIV protease substrate binding site and appears to be responsible for its favorable antiretroviral characteristics.
authors: Departments of Infectious Diseases and Hematology, Kumamoto University School of Medicine, Kumamoto, Japan.
authors: Masayuki
authors: M
authors: Amano
authors: Yasushi
authors: Y
authors: Tojo
authors: Pedro Miguel
authors: PM
authors: Salcedo-Gómez
authors: Joseph Richard
authors: JR
authors: Campbell
authors: Debananda
authors: D
authors: Das
authors: Manabu
authors: M
authors: Aoki
authors: Chun-Xiao
authors: CX
authors: Xu
authors: Kalapala Venkateswara
authors: KV
authors: Rao
authors: Arun K
authors: AK
authors: Ghosh
authors: Hiroaki
authors: H
authors: Mitsuya
mesh_terms: D000595:Amino Acid Sequence; D000069446:Atazanavir Sulfate; D001665:Binding Sites; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D000069454:Darunavir; D024882:Drug Resistance, Viral / Q000187:drug effects; D005663:Furans / Q000737:chemistry / Q000494:pharmacology*; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000302:isolation & purification; D006801:Humans; D020128:Inhibitory Concentration 50; D061466:Lopinavir / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D019438:Ritonavir / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D002219:Carbamates; D005663:Furans; C579815:GRL-0519; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D013449:Sulfonamides; D061466:Lopinavir; D000069446:Atazanavir Sulfate; C095108:amprenavir; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D019438:Ritonavir; D000069454:Darunavir
references: HIV Clin Trials. 2008 Nov-Dec;9(6):418-27
references: 19203907
references: Antimicrob Agents Chemother. 2011 Apr;55(4):1717-27
references: 21282450
references: Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):2398-402
references: 7534421
references: Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8675-80
references: 10411934
references: Nat Rev Drug Discov. 2003 Aug;2(8):624-34
references: 12904812
references: N Engl J Med. 2002 Aug 8;347(6):385-94
references: 12167680
references: J Antimicrob Chemother. 2004 Jul;54(1):6-9
references: 15163657
references: J Antimicrob Chemother. 2006 Jan;57(1):4-7
references: 16284223
references: Adv Pharmacol. 2008;56:169-97
references: 18086412
references: Genome Biol. 2002;3(4):REVIEWS3006
references: 11983066
references: J Infect Dis. 2006 Jul 1;194(1):11-9
references: 16741877
references: Clin Microbiol Infect. 2003 Nov;9(11):1077-84
references: 14616723
references: Nat Rev Microbiol. 2003 Dec;1(3):181-90
references: 15035022
references: Annu Rev Biophys Biomol Struct. 1998;27:249-84
references: 9646869
references: Antimicrob Agents Chemother. 2010 Nov;54(11):4903-6
references: 20805393
references: Antimicrob Agents Chemother. 2003 Oct;47(10):3123-9
references: 14506019
references: Biochim Biophys Acta. 2000 Oct 18;1482(1-2):157-71
references: 11058758
references: Biophys Chem. 2003 Sep;105(2-3):221-30
references: 14499894
references: Annu Rev Biochem. 1993;62:543-85
references: 8352596
references: Bioorg Med Chem Lett. 1998 Mar 17;8(6):687-90
references: 9871583
references: J Antimicrob Chemother. 2007 Sep;60(3):461-3
references: 17609196
references: J Med Virol. 2004 Sep;74(1):16-20
references: 15258963
references: Nat Rev Drug Discov. 2002 Jan;1(1):13-25
references: 12119605
references: Clin Infect Dis. 2004 Apr 15;38(8):1159-66
references: 15095223
references: J Biol Chem. 2007 Sep 28;282(39):28709-28720
references: 17635930
references: Antimicrob Agents Chemother. 2010 Aug;54(8):3460-70
references: 20439612
references: Antimicrob Agents Chemother. 2007 Aug;51(8):2701-8
references: 17548498
references: J Virol. 2002 Feb;76(3):1349-58
references: 11773409
references: J Virol. 2010 Nov;84(22):11961-9
references: 20810732
references: PLoS Med. 2011 Jun;8(6):e1001044
references: 21695087
references: J Biol Chem. 2001 Sep 14;276(37):35194-200
references: 11454872
references: Bioorg Med Chem Lett. 1998 Apr 21;8(8):979-82
references: 9871524
references: ChemMedChem. 2010 Nov 8;5(11):1850-4
references: 20827746
references: Antimicrob Agents Chemother. 2007 Jun;51(6):2143-55
references: 17371811
references: J Org Chem. 2004 Nov 12;69(23):7822-9
references: 15527257
references: J Virol. 2012 Dec;86(24):13384-96
references: 23015723
references: J Antimicrob Chemother. 2010 Jun;65(6):1094-9
references: 20418273