Optimizing the binding affinity of a carrier protein: a case study on the interaction between soluble ifnar2 and interferon beta.

Prolonging the circulatory half-life of low mass protein drugs can be achieved either by administration of a pro-drug or through co-injection with a carrier protein that will slowly release the active protein. The rate of release is concentration and affinity dependent. The optimal relationship between these two in prolonging the half-life of a pro-drug is the focus of this work.

Ligand effects on the binding of cis- and trans-[PtCl(2)Am(1)Am(2)] to proteins.

As part of a systematic study of the basic principles that govern the formation and reactivity of Pt-protein adducts, we report the effect of substituting the amine ligand of cis- and trans-[PtCl(2)(NH(3))(2)] complexes with bulkier planar aromatic or nonplanar cyclic amine ligands on the binding properties of the complexes to ubiquitin and to horse heart myoglobin. The ligand replacement had a different effect on the cis or trans isomers investigated. In the cis-Pt complexes, replacing one or both amine ligands by piperidine or 4-picoline dramatically decreased the binding of the complexes to the proteins studied, whereas in the substituted trans-Pt complexes replacement of the amine by a piperidine or 4-picoline increased the binding rate.

Interactions of cisplatin and transplatin with proteins. Comparison of binding kinetics, binding sites and reactivity of the Pt-protein adducts of cisplatin and transplatin towards biological nucleophiles.

In this manuscript we report on the interactions of cis-DDP (cisplatin, cis-diamminedichloroplatinum(II)) and trans-DDP (transplatin, trans-diamminedichloroplatinum(II)) with two model proteins, ubiquitin (Ub) and horse heart myoglobin (Mb), and attempt to answer the question whether proteins that have methionine-Pt adducts can transfer the platinum to biological nucleophiles and particularly to DNA. Our study shows that cisplatin and transplatin form different adducts with ubiquitin: transplatin forms one major adduct, trans-[Pt(Ub)(NH(3))(2)Cl], while cisplatin forms four distinct adducts, [Pt(Ub)(NH(3))(2)Cl], [Pt(Ub)(NH(3))(2)(H(2)O)], [Pt(Ub)(NH(3))(2)], and [Pt(Ub)(NH(3))]. When binding ubiquitin, Met1 is the preferred binding site of cisplatin, but not of transplatin.

Characterization of sterically stabilized cisplatin liposomes by nuclear magnetic resonance.

Extensive scientific efforts are directed towards finding new and improved platinum anticancer agents. A promising approach is the encapsulation of cisplatin in sterically stabilized, long circulating, PEGylated 100 nm liposomes. This liposomal cisplatin (STEALTH cisplatin, formerly known as SPI-77) shows excellent stability in plasma and has a longer circulation time, greater efficacy and lower toxicity than much free cisplatin.

Effects of monofunctional platinum binding on the thermal stability and conformation of a self-complementary 22-mer.

We investigated the effect of various monofunctional platinum complexes on the thermal stability and conformation of a self-complementary 22-mer duplex oligonucleotide by means of CD and UV melting profiles. We studied several families of triamine complexes of the general formula PtA2AmCl where A2=(NH3)2 and ethylenediamine and where Am=N1-4-methyl-pyridine, N7-guanosine, and 9-ethyl-guanine. Platination by the N1-4-methyl-pyridine and 9-ethyl-guanine complexes led to a decrease in the Tm of the oligonucleotide by 2-11.

Monofunctional platinum amine complexes destabilize DNA significantly.

Both cis-[Pt(NH3)2(4-Me-Py)Cl]+ and trans-[Pt(NH3)2(4-Me-Py)Cl]+ bind DNA covalently at the N7 site of guanine residues forming mono-dentate adducts. However, like cisplatin and transplatin, only the cis isomer has anti-cancer activity, whereas the trans-isomer does not. In order to understand the molecular basis of the different activities associated with cis-[Pt(NH3)2(4-Me-Py)Cl]+ and trans-[Pt(NH3)2(4-Me-Py)Cl]+, the interactions of these two platinum compounds with the DNA heptamer CCTG*TCC:GGACAGG duplex (G* is the platinated guanine) have been examined.