Document Detail

The influence of charge clustering on the anti-HIV-1 activity and in vivo distribution of negatively charged albumins.
MedLine Citation:
PMID:  12007569     Owner:  NLM     Status:  MEDLINE    
The substitution of human serum albumin with negatively charged molecules, such as succinic acid (Suc-HSA) or aconitic acid (Aco-HSA), resulted in proteins with potent anti-HIV activities, by binding to viral gp120 (V3 loop). The aim of the present study was to investigate whether the distribution of negative charges on the albumin backbone influences the anti-HIV activity. Therefore, we prepared albumins with clusters of negatively charged groups by coupling of heparin. The effects of this substitution on anti-HIV activity, in vivo distribution and the protein structure as compared to random succinylation were assessed. In vitro studies indicated that HSA-modified with heparin 6 or 13 kD displayed anti-HIV activity (IC50=660 and 37 nM, respectively) and exhibited affinity for gp120-V3 loop, although the activity was lower than that of Suc-HSA. Combined derivatization of HSA with heparin 13 kD and aconitic acid groups resulted in significantly increased inhibitory actions (IC50=2.8 nM). Structural analysis showed that modification of HSA with heparin did not lead to extensive unfolding of the protein, meaning that these modified proteins were still globular in structure. In contrast, succinylation of HSA resulted in a highly randomly coiled conformation. Dynamic light scattering experiments revealed that, at neutral pH, the heparin fragments attached to the protein were wrapped around the molecule rather than sticking out into the solution. In conclusion, coupling of sufficient clustered negative charges, by coupling of Hep-fragments, on HSA resulted in a clear anti-HIV activity of the protein. Yet, random distribution of anionic groups in the albumin seemed more optimal for in vitro anti-HIV activity. The higher plasma and lymphatic concentrations of Hep-HSA compared to Suc-HSA seemed more favorable for an anti-HIV activity in vivo.
Leonie Beljaars; René Floris; Ben Berkhout; Catharina Smit; Dirk K F Meijer; Grietje Molema
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biochemical pharmacology     Volume:  63     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2002 May 
Date Detail:
Created Date:  2002-05-14     Completed Date:  2002-07-10     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1663-73     Citation Subset:  IM    
Department of Pharmacokinetics and Drug Delivery, University Center for Pharmacy, Groningen University Institute for Drug Exploration (GUIDE), Ant. Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
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MeSH Terms
Aconitic Acid / analogs & derivatives*,  chemistry,  pharmacokinetics,  pharmacology*
Anti-HIV Agents / chemistry,  pharmacokinetics,  pharmacology*
Anticoagulants / metabolism,  pharmacology
Binding Sites
Calorimetry, Differential Scanning
HIV Envelope Protein gp120 / metabolism
HIV-1 / drug effects*
Heparin / analogs & derivatives*,  chemistry*,  pharmacology*
Magnetic Resonance Spectroscopy
Models, Animal
Protein Conformation
Rats, Wistar
Serum Albumin / chemistry,  pharmacokinetics,  pharmacology*
Succinic Acid / chemistry,  pharmacology*
Succinic Acids*
Tissue Distribution
Reg. No./Substance:
0/Anti-HIV Agents; 0/Anticoagulants; 0/HIV Envelope Protein gp120; 0/Hep-HSA; 0/Serum Albumin; 0/Suc-HSA; 0/Succinic Acids; 0/polyaconitylated human serum albumin; 110-15-6/Succinic Acid; 499-12-7/Aconitic Acid; 9005-49-6/Heparin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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