title: Interaction of the HIV NCp7 Protein with Platinum(II) and Gold(III) Complexes Containing Tridentate Ligands.
abstract: The human immunodeficiency virus (HIV) nucleocapsid protein (NCp7) plays significant roles in the virus life cycle and has been targeted by compounds that could lead to its denaturation or block its interaction with viral RNA. Herein, we describe the interactions of platinum(II) and gold(III) complexes with NCp7 and how the reactivity/affinity of potential inhibitors can be modulated by judicious choice of ligands. The interactions of [MCl(N3)]n+(M = Pt2+(n = 1) and Au3+(n = 2); N3= tridentate chelate ligands: bis(2-pyridylmethyl)methylamine (Mebpma, L1) and bis(2-pyridylmethyl)amine (bpma, L2) with the C-terminal zinc finger of NCp7 (ZF2) were investigated by electrospray ionization-mass spectroscopy (ESI-MS). Mass spectra from the incubation of [MCl(Mebpma)]n+complexes (PtL1and AuL1) with ZF2 indicated that they were more reactive than the previously studied diethylenetriamine-containing analogues [MCl(dien)]n+. The initial product of reaction of PtL1with ZF2 results in loss of all ligands and release of zinc to give the platinated apopeptide {PtF} (F = apopeptide). This is in contrast to the incubation with [PtCl(dien)]+, in which {Pt(dien)}-peptide adducts are observed. Incubation of the Au3+complex AuL1with ZF2 gave AuxFn+species (x = 1, 2, 4, F = apopeptide) again with loss of all ligands. Furthermore, the formally substitution-inert analogues [Pt(N3)L]2+(L = 4-methylpyridine (4-pic), 4-dimethylaminopyridine (dmap), and 9-ethylguanine (9-EtGua)) were prepared to examine stacking interactions with N-acetyltryptophan (N-AcTrp), the Trp-containing ZF2, and the "full" two-finger NCp7 itself using fluorescence quenching titration. Use of bpma and Mebpma gave slightly higher affinity than analogous [Pt(dien)L)]2+complexes. The dmap-containing complexes (PtL1a and PtL2a) had the greatest association constants (Ka) for N-AcTrp and ZF2 peptide. The complex PtL1a had the highest Kawhen compared with other known Pt2+analogues: [Pt(dien)(9-EtGua)]2+< [Pt(bpma)(9-EtGua)]2+< [Pt(dien)(dmap)]2+< PtL2a < PtL1a. A Kavalue of ca. 40.6 ± 1.0 × 103M-1was obtained for the full NCp7 peptide with PtL1a. In addition, the mass spectrum of the interaction between ZF2 and PtL1a confirms formation of a 1:1 PtL1a/ZF2 adduct. The reactivity of selected complexes with sulfur-containing amino acid N-acetylcysteine (N-AcCys) was also investigated by195Pt and1H NMR spectroscopy and ESI-MS. The precursor compounds [PtCl(N3)]+PtL1and PtL2reacted readily, whereas their [Pt(N3)L]2+analogues PtL1a and PtL2a were inert to substitution.
authors.affiliation: Chemistry Institute, Fluminense Federal University , Campus Valonguinho, CEP 24020-141, Niterói-RJ, Brazil.|Department of Chemistry, Virginia Commonwealth University , 1001 W. Main St., Richmond, Virginia 23284-2006, United States.
authors.forename: Victor H F
authors.initials: VH
authors.lastname: Bernardes
authors.affiliation: Department of Chemistry, Virginia Commonwealth University , 1001 W. Main St., Richmond, Virginia 23284-2006, United States.
authors.forename: Yun
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Chemistry, Virginia Commonwealth University , 1001 W. Main St., Richmond, Virginia 23284-2006, United States.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Du
authors.affiliation: Department of Chemistry, Virginia Commonwealth University , 1001 W. Main St., Richmond, Virginia 23284-2006, United States.
authors.forename: James
authors.initials: J
authors.lastname: Beaton
authors.affiliation: Chemistry Institute, Fluminense Federal University , Campus Valonguinho, CEP 24020-141, Niterói-RJ, Brazil.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Vargas
authors.affiliation: Department of Chemistry, Virginia Commonwealth University , 1001 W. Main St., Richmond, Virginia 23284-2006, United States.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Farrell
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology; D006046:Gold / Q000737:chemistry* / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008744:Methylamines / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010984:Platinum / Q000737:chemistry* / Q000494:pharmacology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D019380:Anti-HIV Agents; D056831:Coordination Complexes; D008024:Ligands; D008744:Methylamines; C071884:NCP7 protein, Human immunodeficiency virus 1; D054301:gag Gene Products, Human Immunodeficiency Virus; C045319:4-pyridylmethylamine; D010984:Platinum; D006046:Gold