Four novel bis-(naphtho-gamma-pyrones) isolated from Fusarium species as inhibitors of HIV-1 integrase.
Integration of viral DNA into host cell DNA is an essential step in retroviral (HIV-1) replication and is catalyzed by HIV-1 integrase. HIV-1 integrase is a novel therapeutic target and is the focus of efforts to identify effective inhibitors that will prevent/or cure HIV infections. Four novel naphtho-gamma-pyrones, belonging to the chaetochromin and ustilaginoidin family, were discovered as inhibitors of HIV-1 integrase from the screening of fungal extracts using a recombinant in vitro assay. These compounds inhibit both the coupled and strand transfer activity of HIV-1 integrase with IC(50) values of 1-3 and 4-12 microM, respectively. The discovery, structure elucidation, chemical modification and the structure-activity relationship of these compounds are described.
Singh
Sheo B
SB
Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. sheo_singh@merck.com
Zink
Deborah L
DL
Bills
Gerald F
GF
Teran
Ana
A
Silverman
Keith C
KC
Lingham
Russell B
RB
Felock
Peter
P
Hazuda
Daria J
DJ
D019380:Anti-HIV Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D005670:Fusarium / Q000737:chemistry*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D013058:Mass Spectrometry; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D011714:Pyrans; D011753:Pyrones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D011714:Pyrans; D011753:Pyrones; C032678:chaetochromin