Mechanism by which the lectin actinohivin blocks HIV infection of target cells Export

@article{citeulike:5700510, abstract = {10.1073/pnas.0907572106 Various lectins have attracted attention as potential microbicides to prevent HIV transmission. Their capacity to bind glycoproteins has been suggested as a means to block HIV binding and entry into susceptible cells. The previously undescribed lectin actinohivin (AH), isolated by us from an actinomycete, exhibits potent in vitro anti-HIV activity by binding to high-mannose (Man) type glycans (HMTGs) of gp120, an envelope glycoprotein of HIV. AH contains 114 aa and consists of three segments, all of which need to show high affinity to gp120 for the anti-HIV characteristic. To generate the needed mechanistic understanding of AH binding to HIV in anticipation of seeking approval for human testing as a microbicide, we have used multiple molecular tools to characterize it. AH showed a weak affinity to Man\^{I}±(1\^{a}€“2)Man, Man\^{I}±(1\^{a}€“2)Man\^{I}±(1\^{a}€“2)Man, of HMTG (Man8 or Man9) or RNase B (which has a single HMTG), but exhibited a strong and highly specific affinity ( = 3.4 \~{A}— 10 M) to gp120 of HIV, which contains multiple Man8 and/or Man9 units. We have compared AH to an alternative lectin, cyanovirin-N, which did not display similar levels of discrimination between high- and low-density HMTGs. X-ray crystal analysis of AH revealed a 3D structure containing three sugar-binding pockets. Thus, the strong specific affinity of AH to gp120 is considered to be due to multivalent interaction of the three sugar-binding pockets with three HMTGs of gp120 via the \^{a}€œcluster effect\^{a}€ of lectin. Thus, AH is a good candidate for investigation as a safe microbicide to help prevent HIV transmission.}, author = {Tanaka, Haruo and Chiba, Harumi and Inokoshi, Junji and Kuno, Atsushi and Sugai, Takahiro and Takahashi, Atsushi and Ito, Yukishige and Tsunoda, Masaru and Suzuki, Kaoru and Tak\~{A}{\copyright}naka, Akio and Sekiguchi, Takeshi and Umeyama, Hideaki and Hirabayashi, Jun and \r{A}Œmura, Satoshi}, citeulike-article-id = {5700510}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0907572106}, citeulike-linkout-1 = {http://www.pnas.org/content/106/37/15633.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/106/37/15633.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/19717426}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=19717426}, day = {15}, doi = {10.1073/pnas.0907572106}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences}, keywords = {actinohivin, hiv, lectin}, month = {September}, number = {37}, pages = {15633--15638}, posted-at = {2009-09-01 20:14:26}, priority = {0}, title = {Mechanism by which the lectin actinohivin blocks HIV infection of target cells}, url = {http://dx.doi.org/10.1073/pnas.0907572106}, volume = {106}, year = {2009} }

TY - JOUR ID - citeulike:5700510 L3 - citeulike-article-id:5700510 N2 - 10.1073/pnas.0907572106 Various lectins have attracted attention as potential microbicides to prevent HIV transmission. Their capacity to bind glycoproteins has been suggested as a means to block HIV binding and entry into susceptible cells. The previously undescribed lectin actinohivin (AH), isolated by us from an actinomycete, exhibits potent in vitro anti-HIV activity by binding to high-mannose (Man) type glycans (HMTGs) of gp120, an envelope glycoprotein of HIV. AH contains 114 aa and consists of three segments, all of which need to show high affinity to gp120 for the anti-HIV characteristic. To generate the needed mechanistic understanding of AH binding to HIV in anticipation of seeking approval for human testing as a microbicide, we have used multiple molecular tools to characterize it. AH showed a weak affinity to Manα(1–2)Man, Manα(1–2)Manα(1–2)Man, of HMTG (Man8 or Man9) or RNase B (which has a single HMTG), but exhibited a strong and highly specific affinity ( = 3.4 × 10 M) to gp120 of HIV, which contains multiple Man8 and/or Man9 units. We have compared AH to an alternative lectin, cyanovirin-N, which did not display similar levels of discrimination between high- and low-density HMTGs. X-ray crystal analysis of AH revealed a 3D structure containing three sugar-binding pockets. Thus, the strong specific affinity of AH to gp120 is considered to be due to multivalent interaction of the three sugar-binding pockets with three HMTGs of gp120 via the “cluster effect” of lectin. Thus, AH is a good candidate for investigation as a safe microbicide to help prevent HIV transmission. IS - 37 JF - Proceedings of the National Academy of Sciences SN - 1091-6490 EP - 15638 TI - Mechanism by which the lectin actinohivin blocks HIV infection of target cells VL - 106 SP - 15633 KW - actinohivin KW - hiv KW - lectin AU - Tanaka, Haruo AU - Chiba, Harumi AU - Inokoshi, Junji AU - Kuno, Atsushi AU - Sugai, Takahiro AU - Takahashi, Atsushi AU - Ito, Yukishige AU - Tsunoda, Masaru AU - Suzuki, Kaoru AU - Takénaka, Akio AU - Sekiguchi, Takeshi AU - Umeyama, Hideaki AU - Hirabayashi, Jun AU - Ōmura, Satoshi PY - 2009/09/15/ UR - http://dx.doi.org/10.1073/pnas.0907572106 ER -