Metalloporphyrin probes for antimalarial drug action

• Published in: Journal of inorganic biochemistry Vol. 96; no. 4; pp. 478 - 486
• Main Authors: Ziegler, James, Pasierb, Lisa, Cole, Kelly A., Wright, David W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2003
• Subjects: Antimalarials; Antimalarials - chemistry; Antimalarials - metabolism; Antimalarials - pharmacology; Hemeproteins - antagonists & inhibitors; Hemeproteins - metabolism; Hemozoin; Malaria; Metalloporphyrins; Metalloporphyrins - chemistry; Metalloporphyrins - metabolism; Protein Binding; Protoporphyrins - chemistry; Protoporphyrins - metabolism; Spectrophotometry, Ultraviolet; β-Hematin; Antimalarials; β-Hematin; Metalloporphyrins; Malaria; Hemozoin
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/S0162-0134(03)00253-8

Metal-substituted protoporphyrin IXs (Co(III)PPIX ( 1), Cr(III)PPIX ( 2), Mn(III)PPIX ( 3), Cu(II)PPIX ( 4), Mg(II)PPIX ( 5), Zn(II)PPIX ( 6) and Sn(IV)PPIX ( 7)), phthalocyanine tetrasulfonates (PcS ( 8) and Ni(II)PcS ( 9)), and anionic and cationic porphyrins ( meso-tetra(4-sulfonatophenyl)porphine (TPPS4, 10), meso-tetra(4-carboxyphenyl)porphine (TPPC4, 11), tetrakis(4- N-trimethylaminophenyl)porphine (TMAP, 12) and meso-tetra( N-methyl-4-pyridyl)porphine (TMPyP4, 13)) have been used as probes to compare two different assays for the inhibition of β-hematin formation. The results demonstrate that the efficacy of these probes in either the β-hematin inhibition assay ( 9, 7, 6, 5> 4> 11, 3> 10, 8> 2, 1; 12 and 13 did not inhibit.) or the bionucleating template assay ( 8> 1> 11> 9, 2> 4> 3> 7> 10> 5> 6; 12 and 13 did not inhibit.) differ significantly. These differences are examined in light of possible interactions between the inhibitor probes, heme, β-hematin and the bionucleating template. This detailed analysis highlights the fact that while dominant modes of interactions may be occasionally identified, the precise mechanism of inhibition undoubtedly consists of the interplay between multiple interactions.