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(N)] (M = Pt (n = 1) and Au (n = 2); N = tridentate chelate ligands: bis(2-pyridylmethyl)methylamine (Mebpma, L) and bis(2-pyridylmethyl)amine (bpma, L) 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)] complexes (PtL and AuL) with ZF2 indicated that they were more reactive than the previously studied diethylenetriamine-containing analogues [MCl(dien)]. The initial product of reaction of PtL with 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 Au complex AuL with ZF2 gave AuF species (x = 1, 2, 4, F = apopeptide) again with loss of all ligands. Furthermore, the formally substitution-inert analogues [Pt(N)L] (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)] complexes. The dmap-containing complexes (PtLa and PtLa) had the greatest association constants (K) for N-AcTrp and ZF2 peptide. The complex PtLa had the highest K when compared with other known Pt analogues: [Pt(dien)(9-EtGua)] < [Pt(bpma)(9-EtGua)] < [Pt(dien)(dmap)]< PtLa < PtLa. A K value of ca. 40.6 ± 1.0 × 10 M was obtained for the full NCp7 peptide with PtLa. In addition, the mass spectrum of the interaction between ZF2 and PtLa confirms formation of a 1:1 PtLa/ZF2 adduct. The reactivity of selected complexes with sulfur-containing amino acid N-acetylcysteine (N-AcCys) was also investigated by Pt andH NMR spectroscopy and ESI-MS. The precursor compounds [PtCl(N)] PtL and PtL reacted readily, whereas their [Pt(N)L] analogues PtLa and PtLa were inert to substitution.