title: Novel, negatively charged, human serum albumins display potent and selective in vitro anti-human immunodeficiency virus type 1 activity.
abstract: We prepared a series of modified proteins and peptides by derivatizing the positively charged epsilon-amino groups of the lysine amino acids through reaction with anhydrides of succinic acid (Suc) and aconitic acid (Aco). Human serum albumin (HSA) was modified by introduction of a single carboxylic group (Suc-HSA) or two carboxylic groups (Aco-HSA) per amine function, yielding strongly negatively charged compounds. The in vitro anti-human immunodeficiency virus (HIV)-1 IC50 of Suc-HSA was about 1 microgram/ml, and the most polyanionic modified albumin of the series (Aco-HSA) exhibited an IC50 as low as 0.02 microgram/ml. Similar derivatization of the plasma protein orosomucoid or the synthetic polypeptide polylysine did not produce compounds with significant anti-HIV-1 activity, indicating an HSA-specific effect. The mechanism of action of Suc-HSA was reported to be the inhibition of a post-binding virus-cell fusion event, probably due to interference with the gp41-mediated fusion process. In the present study we demonstrate that the more potent Aco-HSA also interferes with this fusion process but, additionally, this compound inhibits (i) the binding of soluble CD4 to HIV-infected cells, (ii) the binding of HIV particles to MT-4 cells, and (iii) the binding of anti-gp120 monoclonal antibody to the gp120 molecule. This indicates that Aco-HSA, apart from post-binding fusion, also inhibits virus-cell binding by shielding viral gp120. The simultaneous inhibition of binding and fusion may lead to a synergistic effect, explaining the extreme potency of Aco-HSA. The polyanionic HSAs are significantly less active against HIV-2 and do not interfere with the replication of feline immunodeficiency virus or 12 other DNA or RNA viruses, indicating a HIV-1-specific effect. In contrast, another polyanionic compound, the sulfated polysaccharide dextran sulfate, inhibits the replication of various viruses in a more nonspecific way, as a general polyanion. Dextran sulfate also exhibits strong anticoagulant activity, whereas Suc-HSA and Aco-HSA do not show this unwanted side effect.
authors.affiliation: Department of Pharmacology and Therapeutics, University Centre for Pharmacy, Groningen State University, The Netherlands.
authors.forename: R W
authors.initials: RW
authors.lastname: Jansen
authors.forename: D
authors.initials: D
authors.lastname: Schols
authors.forename: R
authors.initials: R
authors.lastname: Pauwels
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: D K
authors.initials: DK
authors.lastname: Meijer
mesh_terms: D000838:Anions; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D015704:CD4 Antigens / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D002264:Carboxylic Acids / Q000737:chemistry; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004267:DNA Viruses / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008239:Lysine / Q000737:chemistry; D012328:RNA Viruses / Q000187:drug effects; D012709:Serum Albumin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000838:Anions; D000925:Anticoagulants; D000998:Antiviral Agents; D015704:CD4 Antigens; D002264:Carboxylic Acids; D015699:HIV Envelope Protein gp120; D012709:Serum Albumin; D008239:Lysine