title: The high mannose-type glycan binding lectin actinohivin: dimerization greatly improves anti-HIV activity.
abstract: The actinomycete-derived lectin actinohivin (AH) inhibits entry of HIV-1 to susceptible cells at low nM concentrations. The cooperative binding of three segments of AH to three high mannose-type glycans (HMTGs) of HIV-1 gp120 generates specific and strong anti-HIV activity. Dimerization of AH effectively improves anti-HIV activity by increasing the number of HMTG-binding pockets. AH dimers were prepared using an Escherichia coli expression system and their anti-syncytium formation and anti-HIV activities were evaluated. Each dimer was constructed by a head-to-tail fusion of two AH molecules, with or without a spacer. As a result, His-TEV-AH/RTB(132-143)/AH, which has the residues 132-143 of ricin toxin B-chain (RTB) as a spacer, had 20-fold higher anti-syncytium formation activity and also exhibited 2-30-fold higher anti-HIV activity than AH against various clinically isolated HIV-1 strains, including drug-resistant ones. Mutation analysis implies that all six HMTG-binding pockets of the dimer participated in HMTG binding. Several AH dimers with different spacer sequences showed diverse activities, suggesting that the spacer sequence is an important factor to create higher anti-HIV activity. A dimer with improved anti-HIV activity would be a good candidate for investigation as a potential microbicide to prevent HIV transmission.
authors.affiliation: Faculty of Pharmacy and College of Science and Engineering, Iwaki Meisei University, 5-5-1 Chuodai-Iino, Iwaki, Fukushima, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Junji
authors.initials: J
authors.lastname: Inokoshi
authors.forename: Atsuko
authors.initials: A
authors.lastname: Hachiya
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Omura
authors.forename: Haruo
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D004926:Escherichia coli / Q000235:genetics; D015726:Giant Cells / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D037102:Lectins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008358:Mannose / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D011134:Polysaccharides / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D001426:Bacterial Proteins; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D037102:Lectins; D011134:Polysaccharides; D011993:Recombinant Fusion Proteins; C424136:actinohivin protein, actinomycete; C514793:gp120 protein, Human immunodeficiency virus 1; D008358:Mannose