Incorporation of Privileged Structures into Bevirimat Can Improve Activity against Wild-Type and Bevirimat-Resistant HIV-1.
Two "privileged fragments", caffeic acid and piperazine, were integrated into bevirimat producing new derivatives with improved activity against HIV-1/NL4-3 and NL4-3/V370A carrying the most prevalent bevirimat-resistant polymorphism. The activity of one of these, 18c, was increased by 3-fold against NL4-3 and 51-fold against NL4-3/V370A. Moreover, 18c is a maturation inhibitor with improved metabolic stability. Our study suggested that integration of privileged motifs into promising natural product skeletons is an effective strategy for discovering potent derivatives.
Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina , Chapel Hill, North Carolina 27599-7568, United States.
Yu
Y
Zhao
Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina , Chapel Hill, North Carolina 27599-7568, United States.|Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, People's Republic of China.
Qiong
Q
Gu
Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina , Chapel Hill, North Carolina 27599-7568, United States.
Susan L
SL
Morris-Natschke
Surgical Oncology Research Facility, Duke University Medical Center , Box 2926, Durham, North Carolina 27710, United States.
Chin-Ho
CH
Chen
Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina , Chapel Hill, North Carolina 27599-7568, United States.|Chinese Medicine Research and Development Center, China Medical University and Hospital , 404 Taichung, Taiwan.
Kuo-Hsiung
KH
Lee
D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D019556:COS Cells; D002109:Caffeic Acids / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002522:Chlorocebus aethiops; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology*; D013386:Succinates / Q000737:chemistry* / Q000494:pharmacology*; D014315:Triterpenes / Q000737:chemistry* / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects; D053978:Pentacyclic Triterpenes
D019380:Anti-HIV Agents; D002109:Caffeic Acids; D000077489:Piperazine; D010879:Piperazines; D013386:Succinates; D014315:Triterpenes; C479935:bevirimat; D053978:Pentacyclic Triterpenes; C040048:caffeic acid
Open Med Chem J. 2014 Sep 03;8:23-7
25250097
Med Res Rev. 2001 Sep;21(5):412-49
11579441
J Med Chem. 2009 May 28;52(10):3248-58
19388685
J Med Chem. 2004 May 6;47(10):2405-8
15115380
J Nat Prod. 2010 Mar 26;73(3):500-16
20187635
Curr Med Chem. 2005;12(15):1811-8
16029149
ACS Med Chem Lett. 2015 Feb 09;6(3):229-34
25941544
Antimicrob Agents Chemother. 2015 Oct 19;60(1):190-7
26482309
J Med Chem. 2016 Apr 14;59(7):2849-78
26509831
J Med Chem. 2008 Apr 24;51(8):2575-9
18351727
J Med Chem. 2013 Mar 14;56(5):2029-37
23379607
Mini Rev Med Chem. 2013 Oct;13(11):1579-601
23895191
Antimicrob Agents Chemother. 2007 Sep;51(9):3063-6
17576843
J Med Chem. 2012 Sep 27;55(18):8128-36
22978745
Eur J Med Chem. 2013 Apr;62:453-65
23399723
Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13555-60
14573704
J Med Chem. 2002 Jun 6;45(12):2615-23
12036371
J Am Chem Soc. 2009 Dec 9;131(48):17536-7
19950987
Drug Des Devel Ther. 2015 Sep 03;9:5051-60
26366056
Antimicrob Agents Chemother. 2007 Oct;51(10):3574-81
17638699
Mini Rev Med Chem. 2011 Jul;11(8):695-713
21679136
Antimicrob Agents Chemother. 2008 Jan;52(1):128-36
17954689
J Med Chem. 1988 Dec;31(12):2235-46
2848124
J Med Chem. 1996 Mar 1;39(5):1016-7
8676334
J Nat Prod. 1994 Feb;57(2):243-7
8176401
Clin Pharmacokinet. 2007;46(7):589-98
17596104
Nat Prod Rep. 2011 Nov;28(12):1937-55
21979811
Science. 1983 May 20;220(4599):865-7
6601823
Nat Chem Biol. 2008 Nov;4(11):682-90
18936753
J Nat Prod. 2016 Mar 25;79(3):578-83
26756779
Antimicrob Agents Chemother. 2010 Jun;54(6):2345-53
20308382
Chem Rev. 2003 Mar;103(3):893-930
12630855