The Lysosomal Protein Saposin B Binds Chloroquine

Abstract

Chloroquine has been widely used in the treatment of malaria since the 1950’s. CQ is also becoming an important therapeutic compound for the treatment of auto-immune disorders and has shown activity as an anti-cancer agent. The full extent of CQ pharmacology in humans is still unclear. Herein, we demonstrate that the lysosomal protein saposin B, critical for select lipid degradation, binds chloroquine with implications for both chloroquine function and toxicity.

Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection

“…Its three-dimensioanl structure was retrieved from pdb file # 4V2O [19] . CLQ-OH is (RS)-2-[{4-[(7-chloroquinolin-4-yl)amino]pentyl}(ethyl)amino]ethanol.…”

Synthesis of stable isotope–labeled chloroquine and amodiaquine and their metabolites

“…However, there is some notable side effects with the use of amodiaquine, such as hepatotoxicity . In general, antimalarial drugs of this class have shown to cause severe side effects . Therefore, diagnostic monitoring of chloroquine and amodiaquine and their metabolites by quantitative mass spectrometry has found recent increased attention.…”

“…6 In general, antimalarial drugs of this class have shown to cause severe side effects. 7,8 Therefore, diagnostic monitoring of chloroquine and amodiaquine and their metabolites by quantitative mass spectrometry has found recent increased attention. Importantly, stable isotope-labeled (SIL) reference samples have become the gold standard for facilitating accurate measurements and method development for mass spectrometry detection and quantification.…”

Saposin B Binds the Lipofuscin Bisretinoid A2E and Prevents its Enzymatic and Photooxidation

“…[10] We have been interested in the multisubstrate specificity of human lysosomal Saposin B (SapB) and its implications in drug toxicity and/or disease progression. [11,12] SapB is an intralysosomal, non-enzymatic proteinaceous co-factor that binds and presents 3-Osulfogalactosylceramide (sulfatide) to the active site of arylsulfatase A (ASA) for desulfation to galactosylceramide. [13] The lack of functional SapB (or ASA) results in a buildup of sulfatide and the fatal LSD metachromatic leukodystrophy (MLD).…”