Inhibition of HIV-1 replication by a bis-thiadiazolbenzene-1,2-diamine that chelates zinc ions from retroviral nucleocapsid zinc fingers.
The human immunodeficiency virus type 1 (HIV-1) nucleocapsid p7 (NCp7) protein holds two highly conserved "CCHC" zinc finger domains that are required for several phases of viral replication. Basic residues flank the zinc fingers, and both determinants are required for high-affinity binding to RNA. Several compounds were previously found to target NCp7 by reacting with the sulfhydryl group of cysteine residues from the zinc fingers. Here, we have identified an N,N'-bis(1,2,3-thiadiazol-5-yl)benzene-1,2-diamine (NV038) that efficiently blocks the replication of a wide spectrum of HIV-1, HIV-2, and simian immunodeficiency virus (SIV) strains. Time-of-addition experiments indicate that NV038 interferes with a step of the viral replication cycle following the viral entry but preceding or coinciding with the early reverse transcription reaction, pointing toward an interaction with the nucleocapsid protein p7. In fact, in vitro, NV038 efficiently depletes zinc from NCp7, which is paralleled by the inhibition of the NCp7-induced destabilization of cTAR (complementary DNA sequence of TAR). A chemical model suggests that the two carbonyl oxygens of the esters in this compound are involved in the chelation of the Zn(2+) ion. This compound thus acts via a different mechanism than the previously reported zinc ejectors, as its structural features do not allow an acyl transfer to Cys or a thiol-disulfide interchange. This new lead and the mechanistic study presented provide insight into the design of a future generation of anti-NCp7 compounds.
Pannecouque
Christophe
C
Rega Institute, Katholieke Universiteit Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
Szafarowicz
Beata
B
Volkova
Natalia
N
Bakulev
Vasiliy
V
Dehaen
Wim
W
Mély
Yves
Y
Daelemans
Dirk
D
D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects*; D015032:Zinc / Q000737:chemistry; D016335:Zinc Fingers / Q000187:drug effects; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000187:drug effects
D019380:Anti-HIV Agents; D052160:Benzothiazoles; D002614:Chelating Agents; C071884:NCP7 protein, Human immunodeficiency virus 1; D054301:gag Gene Products, Human Immunodeficiency Virus; D015032:Zinc