Structural and pharmacological evaluation of a novel non-nucleoside reverse transcriptase inhibitor as a promising long acting nanoformulation for treating HIV.
Animals
Anti-HIV Agents
/ chemical synthesis
Crystallography, X-Ray
Drug Delivery Systems
/ methods
Drug Design
HIV Infections
/ drug therapy
HIV Reverse Transcriptase
/ antagonists & inhibitors
HIV-1
/ drug effects
Humans
Mice
Mice, Inbred BALB C
Nanoparticles
/ therapeutic use
Reverse Transcriptase Inhibitors
/ chemical synthesis
HIV-1
Long-acting nanoformulation
Mice model
Non-nucleoside reverse transcriptase inhibitor
Pharmacokinetic studies
X-ray crystallography
Journal
Antiviral research
ISSN: 1872-9096
Titre abrégé: Antiviral Res
Pays: Netherlands
ID NLM: 8109699
Informations de publication
Date de publication:
07 2019
07 2019
Historique:
received:
03
04
2019
accepted:
23
04
2019
pubmed:
30
4
2019
medline:
15
5
2020
entrez:
30
4
2019
Statut:
ppublish
Résumé
Combination antiretroviral therapy (cART) has been proven effective in inhibiting human immunodeficiency virus type 1 (HIV-1) infection and has significantly improved the health outcomes in acquired immune deficiency syndrome (AIDS) patients. The therapeutic benefits of cART have been challenged because of the toxicity and emergence of drug-resistant HIV-1 strains along with lifelong patient compliance resulting in non-adherence. These issues also hinder the clinical benefits of non-nucleoside reverse transcriptase inhibitors (NNRTIs), which are one of the vital components of cART for the treatment of HIV-1 infection. In this study, using a computational and structural based drug design approach, we have discovered an effective HIV -1 NNRTI, compound I (Cmpd I) that is very potent in biochemical assays and which targets key residues in the allosteric binding pocket of wild-type (WT)-RT as revealed by structural studies. Furthermore, Cmpd I exhibited very potent antiviral activity in HIV-1 infected T cells, lacked cytotoxicity (therapeutic index >100,000), and no significant off-target effects were noted in pharmacological assays. To address the issue of non-adherence, we developed a long-acting nanoformulation of Cmpd I (Cmpd I-NP) using poly (lactide-coglycolide) (PLGA) particles. The pharmacokinetic studies of free and nanoformulated Cmpd I were carried out in BALB/c mice. Intraperitoneal administration of Cmpd I and Cmpd I-NP in BALB/c mice revealed prolonged serum residence time of 48 h and 30 days, respectively. The observed serum concentrations of Cmpd I in both cases were sufficient to provide >97% inhibition in HIV-1 infected T-cells. The significant antiviral activity along with favorable pharmacological and pharmacokinetic profile of Cmpd I, provide compelling and critical support for its further development as an anti-HIV therapeutic agent.
Identifiants
pubmed: 31034849
pii: S0166-3542(19)30183-4
doi: 10.1016/j.antiviral.2019.04.010
pmc: PMC6554724
mid: NIHMS1528803
pii:
doi:
Substances chimiques
Anti-HIV Agents
0
Reverse Transcriptase Inhibitors
0
HIV Reverse Transcriptase
EC 2.7.7.49
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
110-116Subventions
Organisme : NIAID NIH HHS
ID : R21 AI122384
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI044616
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI112443
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM049551
Pays : United States
Organisme : NIH HHS
ID : S10 OD018007
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007205
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA141172
Pays : United States
Organisme : NIAID NIH HHS
ID : P50 AI150464
Pays : United States
Organisme : NIAID NIH HHS
ID : R33 AI122384
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI141572
Pays : United States
Organisme : NIH HHS
ID : S10 OD021527
Pays : United States
Organisme : NIBIB NIH HHS
ID : R01 EB000487
Pays : United States
Organisme : NIBIB NIH HHS
ID : R56 EB000487
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM124165
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.
Références
Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3
pubmed: 15299374
PLoS Med. 2015 Apr 07;12(4):e1001810
pubmed: 25849352
PLoS One. 2013 May 28;8(5):e63623
pubmed: 23723990
J Med Virol. 2001 Nov;65(3):445-8
pubmed: 11596076
Bioorg Med Chem Lett. 2013 Sep 15;23(18):5213-6
pubmed: 23937980
Mol Pharmacol. 2017 Apr;91(4):383-391
pubmed: 28167742
Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1466-71
pubmed: 18230722
Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
pubmed: 20383002
ACS Med Chem Lett. 2016 Oct 31;7(12):1156-1160
pubmed: 27994756
N Engl J Med. 2008 May 15;358(20):2095-106
pubmed: 18480202
J Am Chem Soc. 2012 Dec 5;134(48):19501-3
pubmed: 23163887
JAMA. 2016 Jul 5;316(1):70-8
pubmed: 27348249
Mol Pharm. 2015 Dec 7;12(12):4363-74
pubmed: 26529558
Pak J Pharm Sci. 2016 May;29(3):887-94
pubmed: 27166533
Acc Chem Res. 2009 Jun 16;42(6):724-33
pubmed: 19317443
Bioorg Med Chem Lett. 2012 Apr 1;22(7):2376-9
pubmed: 22406117
Nat Rev Drug Discov. 2012 Dec;11(12):909-22
pubmed: 23197038
Acta Crystallogr D Biol Crystallogr. 2009 Oct;65(Pt 10):1074-80
pubmed: 19770504
J Med Chem. 2005 Mar 24;48(6):1901-9
pubmed: 15771434
Eur J Pharm Biopharm. 2019 May;138:75-91
pubmed: 29678735
Bioorg Med Chem Lett. 2015 Nov 1;25(21):4824-4827
pubmed: 26166629
Biomed Microdevices. 2008 Apr;10(2):321-8
pubmed: 18165903
J Am Chem Soc. 2013 Nov 6;135(44):16705-13
pubmed: 24151856
Br J Clin Pharmacol. 2001 Oct;52(4):349-55
pubmed: 11678778
ACS Med Chem Lett. 2015 Aug 31;6(10):1075-9
pubmed: 26487915
Science. 1992 Jun 26;256(5065):1783-90
pubmed: 1377403
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
pubmed: 15572765
ACS Med Chem Lett. 2014 Oct 13;5(11):1259-62
pubmed: 25408842
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):213-21
pubmed: 20124702
Eur J Med Chem. 2015 Mar 6;92:754-65
pubmed: 25626145
Therapie. 1993 Jan-Feb;48(1):1-5
pubmed: 8356539
Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
pubmed: 20124692
Antiviral Res. 2018 Aug;156:85-91
pubmed: 29885378
Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):293-302
pubmed: 21460447
Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E802-E811
pubmed: 29279368
Elife. 2013 Sep 10;2:e01456
pubmed: 24040512
Chem Biol Drug Des. 2014 May;83(5):541-9
pubmed: 24289305
J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
pubmed: 19461840
Adv Drug Deliv Rev. 2002 Mar 31;54(3):355-66
pubmed: 11922952
J Mol Biol. 1968 Apr 28;33(2):491-7
pubmed: 5700707