Hinnuliquinone, a C2-symmetric dimeric non-peptide fungal metabolite inhibitor of HIV-1 protease.
HIV-1 protease is one of several key enzymes required for the replication and maturation of HIV-1 virus. An almost two-decade research effort by academic and pharmaceutical institutions resulted in the successful commercialization of seven drugs that are potent inhibitors of HIV-1 protease activity and which, if used correctly, are highly effective in managing viral load. However, identification of clinical viral isolates that are resistant to these drugs indicates that this is a significant problem and that new classes of inhibitors are continually needed. Screening of microbial extracts followed by bioassay-guided isolation led to the discovery of a natural hinnuliquinone, a C(2)-symmetric bis-indolyl quinone natural product that inhibited the wild-type and a clinically resistant (A44) strain of HIV-1 protease with K(i) values of 0.97 and 1.25microM, respectively. Crystallographic analysis of the inhibitor-bound HIV-1 protease helped explain the importance of the C(2)-symmetry of hinnuliquinone for activity. Details of the isolation, biological activity, and crystallographic analysis of the inhibitor-bound protease are herein described.
Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA. sheo_singh@merck.com <sheo_singh@merck.com>
Sheo B
SB
Singh
John G
JG
Ondeyka
Nasios
N
Tsipouras
Carolyn
C
Ruby
Vinod
V
Sardana
Marvin
M
Schulman
Manuel
M
Sanchez
Fernando
F
Pelaez
Mark W
MW
Stahlhut
Sanjeev
S
Munshi
David B
DB
Olsen
Russell B
RB
Lingham
D016227:Benzoquinones / Q000737:chemistry* / Q000378:metabolism*; D020134:Catalytic Domain; D019281:Dimerization; D005656:Fungal Proteins / Q000737:chemistry* / Q000378:metabolism*; D015658:HIV Infections / Q000188:drug therapy; D016333:HIV Protease / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000627:therapeutic use; D015497:HIV-1 / Q000201:enzymology; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D029963:Quercus / Q000382:microbiology; D011809:Quinones / Q000737:chemistry / Q000378:metabolism
D016227:Benzoquinones; D005656:Fungal Proteins; D017320:HIV Protease Inhibitors; D007211:Indoles; C119066:L 783281; D011809:Quinones; D016333:HIV Protease; C494428:hinnuliquinone