title: Bifunctional inhibition of human immunodeficiency virus type 1 reverse transcriptase: mechanism and proof-of-concept as a novel therapeutic design strategy.
abstract: Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is a major target for currently approved anti-HIV drugs. These drugs are divided into two classes: nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). This study illustrates the synthesis and biochemical evaluation of a novel bifunctional RT inhibitor utilizing d4T (NRTI) and a TMC-derivative (a diarylpyrimidine NNRTI) linked via a poly(ethylene glycol) (PEG) linker. HIV-1 RT successfully incorporates the triphosphate of d4T-4PEG-TMC bifunctional inhibitor in a base-specific manner. Moreover, this inhibitor demonstrates low nanomolar potency that has 4.3-fold and 4300-fold enhancement of polymerization inhibition in vitro relative to the parent TMC-derivative and d4T, respectively. This study serves as a proof-of-concept for the development and optimization of bifunctional RT inhibitors as potent inhibitors of HIV-1 viral replication.
authors: Department of Pharmacology, School of Medicine, Yale University, New Haven, Connecticut 06520, USA.
authors: Christopher M
authors: CM
authors: Bailey
authors: Todd J
authors: TJ
authors: Sullivan
authors: Pinar
authors: P
authors: Iyidogan
authors: Julian
authors: J
authors: Tirado-Rives
authors: Raymond
authors: R
authors: Chung
authors: Juliana
authors: J
authors: Ruiz-Caro
authors: Ebrahim
authors: E
authors: Mohamed
authors: William L
authors: WL
authors: Jorgensen
authors: William
authors: W
authors: Jorgensen
authors: Roger
authors: R
authors: Hunter
authors: Karen S
authors: KS
authors: Anderson
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017931:DNA Primers; D015226:Dinucleoside Phosphates / Q000737:chemistry / Q000302:isolation & purification; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D013058:Mass Spectrometry; D008958:Models, Molecular; D009841:Oligonucleotides / Q000737:chemistry / Q000302:isolation & purification; D011092:Polyethylene Glycols / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects; D014961:X-Ray Diffraction
chemical_list: D019380:Anti-HIV Agents; D017931:DNA Primers; D015226:Dinucleoside Phosphates; D007202:Indicators and Reagents; D009841:Oligonucleotides; D018894:Reverse Transcriptase Inhibitors; D011092:Polyethylene Glycols; D054303:HIV Reverse Transcriptase
references: FEBS Lett. 1991 Oct 7;291(1):1-5
references: 1718777
references: Viruses. 2010 Apr;2(4):880-99
references: 21994659
references: Bioorg Med Chem Lett. 2013 Mar 1;23(5):1511-8
references: 23380374
references: J Med Chem. 2004 May 6;47(10):2550-60
references: 15115397
references: Science. 1995 Feb 17;267(5200):988-93
references: 7532321
references: Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1466-71
references: 18230722
references: Nucleosides Nucleotides Nucleic Acids. 2000 Sep;19(9):1441-61
references: 11092314
references: Biochim Biophys Acta. 2010 May;1804(5):1213-22
references: 20083238
references: J Biol Chem. 2004 Feb 20;279(8):6221-4
references: 14722107
references: Nucleosides Nucleotides. 1999 Apr-May;18(4-5):883-4
references: 10432702
references: Mitochondrion. 2004 Jul;4(2-3):203-13
references: 16120386
references: J Med Chem. 2012 Apr 26;55(8):3595-613
references: 22268494
references: J Virol. 2003 Oct;77(20):11193-200
references: 14512567
references: Chem Rev. 2000 Jun 14;100(6):2047-60
references: 11749283
references: Bioorg Med Chem Lett. 2001 Sep 3;11(17):2235-9
references: 11527705
references: Science. 1998 Nov 27;282(5394):1669-75
references: 9831551
references: J Control Release. 2005 Sep 20;107(1):143-57
references: 16039001
references: J Comput Chem. 2004 Oct;25(13):1605-12
references: 15264254
references: Biochemistry. 2006 Jun 13;45(23):7334-40
references: 16752922
references: Mitochondrion. 2008 Mar;8(2):181-95
references: 18313992
references: Nucleosides Nucleotides Nucleic Acids. 2001 Sep;20(9):1655-70
references: 11580192
references: Nucleosides Nucleotides Nucleic Acids. 2002;21(8-9):505-33
references: 12484448
references: J Biol Chem. 2003 Sep 19;278(38):36403-9
references: 12857740
references: Mol Cancer Ther. 2008 Oct;7(10):3373-80
references: 18852140
references: J Med Chem. 2005 Mar 24;48(6):1901-9
references: 15771434
references: Chem Pharm Bull (Tokyo). 1997 Mar;45(3):482-6
references: 9085555
references: J Biol Chem. 1982 Sep 10;257(17):10261-6
references: 6286646
references: J Med Chem. 1999 Dec 16;42(25):5188-96
references: 10602704
references: Structure. 1996 Jul 15;4(7):853-60
references: 8805568
references: Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3911-5
references: 7513427
references: Antimicrob Agents Chemother. 2011 Jan;55(1):276-83
references: 21078938
references: Bioorg Med Chem Lett. 2007 May 1;17(9):2614-7
references: 17317163
references: Chemistry. 2003 Oct 6;9(19):4603-10
references: 14566865
references: Nat Struct Biol. 1995 May;2(5):407-15
references: 7545077
references: Antimicrob Agents Chemother. 2000 Jan;44(1):217-21
references: 10602755
references: Antiviral Res. 2012 Aug;95(2):93-103
references: 22664235
references: J Med Chem. 2000 May 18;43(10):1927-39
references: 10821705
references: Biochemistry. 1997 Nov 18;36(46):14064-70
references: 9369478
references: Science. 1996 Mar 15;271(5255):1582-6
references: 8599114
references: Expert Opin Drug Metab Toxicol. 2010 Dec;6(12):1493-504
references: 20929279
references: Antivir Chem Chemother. 1998 May;9(3):205-23
references: 9875400
references: J Mol Biol. 2009 Jan 23;385(3):693-713
references: 19022262
references: Antiviral Res. 2010 Jan;85(1):210-31
references: 19616029
references: J Med Chem. 1995 May 12;38(10):1641-9
references: 7538589
references: Bioorg Med Chem. 2010 Jul 1;18(13):4661-73
references: 20605472
references: Science. 1995 Jan 27;267(5197):483-9
references: 7824947
references: J Gen Virol. 1998 Jun;79 ( Pt 6):1337-45
references: 9634073
references: Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):8046-9
references: 7544013
references: J Am Chem Soc. 2003 May 21;125(20):6016-7
references: 12785806
references: Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4204-9
references: 15010526