title: Regulation of amantadine hydrochloride binding with IIA subdomain of human serum albumin by fatty acid chains.
abstract: Human serum albumin (HSA) is a major protein component of blood plasma that has been exploited to bind and transport a wide variety of endogenous and exogenous organic compounds. Although anionic drugs readily associate with the IIA subdomain of HSA, most cationic drugs poorly associate with HSA at this subdomain. In this study, we propose to improve the association between cationic drugs and HSA by modifying HSA with fatty acid chains. For our experiments, we tested amantadine hydrochloride, a cationic drug with antiviral and antiparkinsonian effects. Our results suggest that extensive myristoylation of HSA can help stabilize the interaction between amantadine and HSA in vitro. Our X-ray crystallography data further elucidate the structural basis of this regulation. Additionally, our crystallography data suggest that anionic drugs, with a functional carboxylate group, may enhance the association between amantadine and HSA by a mechanism similar to myristoylation. Ultimately, our results provide critical structural insight into this novel association between cationic drugs and the HSA IIA subdomain, raising the tempting possibility to fully exploit the unique binding capacity of HSA's IIA subdomain to achieve simultaneous delivery of anionic and cationic drugs.
authors.affiliation: State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China. Guangxi Normal University, Guilin, Guangxi, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Yang
authors.forename: Philbert
authors.initials: P
authors.lastname: Lee
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Ma
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Guoping
authors.initials: G
authors.lastname: Yang
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Wu
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
mesh_terms: D000547:Amantadine / Q000737:chemistry / Q000378:metabolism*; D000978:Antiparkinson Agents / Q000737:chemistry / Q000378:metabolism*; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D002412:Cations; D018360:Crystallography, X-Ray; D004337:Drug Carriers; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009227:Myristic Acids / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism*; D000075462:Serum Albumin, Human; D013050:Spectrometry, Fluorescence
chemical_list: C422455:ALB protein, human; D000978:Antiparkinson Agents; D000998:Antiviral Agents; D002412:Cations; D004337:Drug Carriers; D009227:Myristic Acids; D012709:Serum Albumin; D000547:Amantadine; D000075462:Serum Albumin, Human