Nuclear Localization Signal of HIV-1 as a Novel Target for Therapeutic Intervention

摘要: Human immunodeficiency virus type 1 (HIV-1) is a lentivirus and shares with other members of this retroviral subfamily the ability to replicate in nondividing cells, particular, cells monocyte/macrophage lineage. This feature relies on presence specific nuclear localization signal (NLS) within viral matrix protein (MA p17), which some degree can be complemented by activity vpr gene product. The MA p17 NLS ensures efficient transportation preintegration complex into nucleus an infected macrophage confers persistence HIV-1 quiescent T therefore presents attractive target for therapeutic intervention. Nuclear signals general particular are characterized stretch positively charged amino acids including one or more lysine residues. A series compounds potentially capable binding reacting forming Schiff base adducts was synthesized. Our special consideration make that would preferentially bind two closely contiguous functions, as opposed isolated single We assumed approach might specifically compound while affecting regions less, thus reducing nonspecific cytotoxicity. Antiviral assessed primary monocytes peripheral blood lymphocytes (PBL) HIV-1ADA strain. Viral replication monitored reverse transcriptase (RT) supernatant. Efficiency importation estimated formation 2-LTR circle forms DNA also situ PCR techniques. Arylene bis(methyl ketone) nitrogenous third substituent, especially pyrimidinic side-chain, inhibited human at IC50 low nM. These did not block lymphocyte cultures. inhibitory effect observed monocyte cultures appeared context markedly reduced drug. No cytotoxic effects vitro concentrations high 10 µM. An amidinohydrazone derivative most active about 100 times less than parent, indicating carbonyl groups were instrumental antiviral effect. early results suggest susceptible pharmaceutical intervention targeted against proteins complex. described efficiently translocation nuclei monocytes, inhibit replication. inhibition effective only seen proliferating cultures, such activated PBLs. Thus, drugs may useful arm HIV infection could thereby value treating macrophage-specific manifestations disease, dementia. In combination drugs, potential therapeutics exploiting help control progression disease.