Lectin Engineering, a Molecular Evolutionary Approach to Expanding the Lectin Utilities

Hu, Dan; Tateno, Hiroaki; Hirabayashi, Jun

doi:10.3390/molecules20057637

Cited by 45 publications

(34 citation statements)

References 72 publications

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“…In order to improve their binding properties, researchers have started to focus their efforts on lectin engineering. [92][93][94][95][96][97] Several types of lectins can be used as scaffolds, such as L-type, F-type, Galectins and R-type, with different engineering procedures available (e.g. site-directed mutagenesis, random mutagenesis and DNA shuffle to name a few).…”

Section: Lectinsmentioning

confidence: 99%

“…site-directed mutagenesis, random mutagenesis and DNA shuffle to name a few). 97 Recently, the engineering of a bacterial F-type lectin domain (FLD) from Streptosporangium roseum, namely SrFLD, showed significantly improved binding towards multivalent fucosylated glycoconjugates. 98 The engineered lectin, SrDupFLD, contained a partial duplication of the original FLD sequence, affording two possible L-fucose binding pockets.…”

Section: Lectinsmentioning

confidence: 99%

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The challenges of glycan recognition with natural and artificial receptors

et al. 2019

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Section: Lectinsmentioning

confidence: 99%

Section: Lectinsmentioning

confidence: 99%

The challenges of glycan recognition with natural and artificial receptors

et al. 2019

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“…rBC2LC-N may be a unique lectin that lacks typical hemagglutination activity. However, the rapid improvement in lectin engineering technologies (27) will provide control over the harmful adverse effects of some lectins, and synthetic lectin technologies will permit the development of de novo lectins with ideal characteristics as drug carriers. This study provides new insight into cancer treatments that might serve as alternatives to expensive antibody-based drugs.…”

Section: Discussionmentioning

confidence: 99%

A Novel Therapeutic Strategy for Pancreatic Cancer: Targeting Cell Surface Glycan Using rBC2LC-N Lectin–Drug Conjugate (LDC)

Shimomura

Oda

Tateno

et al. 2018

Molecular Cancer Therapeutics

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Various cancers, including pancreatic ductal adenocarcinoma (PDAC), remain intractable even with costly tumor-targeting antibody drugs. Because the outermost coatings of cancer cells are composed of cell-specific glycan layers (glycocalyx), lectins, proteins with glycan-binding potential, were evaluated for possible use as drug carriers in PDAC treatment. A human PDAC cell line with well-to-moderately differentiated properties (Capan-1) was subjected to lectin microarray analysis to identify specific lectin-glycan pairs. The selected lectin was fused with a bacterial exotoxin for the construction of a lectin-drug conjugate (LDC), and its safety and antitumor effects were evaluated. A specific affinity between a recombinant bacterial C-type lectin (rBC2LC-N) and Capan-1 was identified, and its positivity was confirmed in 69 human samples. In contrast to the belief that all lectins mediate harmful hemagglutination, rBC2LC-N did not cause hemagglutination with human erythrocytes and was safely administered to mice. The 50% inhibitory concentration of LDC to Capan-1 (1.04 pg/mL ¼ 0.0195 pmol/L) was 1/1,000 lower than that reported for conventional immunotoxins. The intraperitoneal administration of LDC reduced the tumor weight from 390 to 130.8 mg (P < 0.01) in an orthotopic model and reduced the number of nodules from 48 to 3 (P < 0.001) and improved survival from 62 to 105 days in a peritoneal dissemination model (P < 0.0001). In addition, the effect of LDC was reproduced in nodules from patient-derived PDAC xenografts through intravenous injection. Herein, we show the concept of utilizing lectins as drug carriers to target glycans on the cancer cell surface, highlighting new insights into cancer treatments.

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“…In the following sub-sections, the authors describe a few examples of protein engineering studies performed in the authors' laboratory to note how the derived results were beyond their expectation: the first two were conducted on an R-type lectin domain, EW29Ch, to which random point mutagenesis was introduced by error-prone polymerase chain reaction followed by expression screening using ribosome display (outline summarized in figure 1) (for a review, see [39]), while the third was based on site-directed mutagenesis targeting sugar-binding residues of a mushroom galectin, ACG, and led to an unexpected result.…”

Section: Current State Of the Art Of Lectin Engineeringmentioning

confidence: 99%

Lectin engineering: the possible and the actual

Hirabayashi

Arai

2019

Interface Focus.

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Lectins are a widespread group of sugar-binding proteins occurring in all types of organisms including animals, plants, bacteria, fungi and even viruses. According to a recent report, there are more than 50 lectin scaffolds (∼Pfam), for which three-dimensional structures are known and sugar-binding functions have been confirmed in the literature, which far exceeds our view in the twentieth century (Fujimoto et al. 2014 Methods Mol. Biol. 1200 , 579–606 ( doi:10.1007/978-1-4939-1292-6_46 )). This fact suggests that new lectins will be discovered either by a conventional screening approach or just by chance. It is also expected that new lectin domains including those found in enzymes as carbohydrate-binding modules will be generated in the future through evolution, although this has never been attempted on an experimental level. Based on the current state of the art, various methods of lectin engineering are available, by which lectin specificity and/or stability of a known lectin scaffold can be improved. However, the above observation implies that any protein scaffold, including those that have never been described as lectins, may be modified to acquire a sugar-binding function. In this review, possible approaches to confer sugar-binding properties on synthetic proteins and peptides are described.

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Lectin Engineering, a Molecular Evolutionary Approach to Expanding the Lectin Utilities

Cited by 45 publications

References 72 publications

The challenges of glycan recognition with natural and artificial receptors

The challenges of glycan recognition with natural and artificial receptors

A Novel Therapeutic Strategy for Pancreatic Cancer: Targeting Cell Surface Glycan Using rBC2LC-N Lectin–Drug Conjugate (LDC)

Lectin engineering: the possible and the actual

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