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2. Functional Divergence in the Affinity and Stability of Non-Canonical Cysteines and Non-Canonical Disulfide Bonds: Insights from a VHH and VNAR Study.

Author

Xu, Mingce, Zhao, Zheng, Deng, Penghui, Sun, Mengsi, Chiu, Cookson K. C., Wu, Yujie, Wang, Hao, and Bi, Yunchen

Subjects
ANTIGEN receptors, MOLECULAR dynamics, CHONDRICHTHYES, REDUCING agents, THERMAL stability
Abstract

Single-domain antibodies, including variable domains of the heavy chains of heavy chain-only antibodies (VHHs) from camelids and variable domains of immunoglobulin new antigen receptors (VNARs) from cartilaginous fish, show the therapeutic potential of targeting antigens in a cytosol reducing environment. A large proportion of single-domain antibodies contain non-canonical cysteines and corresponding non-canonical disulfide bonds situated on the protein surface, rendering them vulnerable to environmental factors. Research on non-canonical disulfide bonds has been limited, with a focus solely on VHHs and utilizing only cysteine mutations rather than the reducing agent treatment. In this study, we examined an anti-lysozyme VNAR and an anti-BC2-tag VHH, including their non-canonical disulfide bond reduced counterparts and non-canonical cysteine mutants. Both the affinity and stability of the VNARs and VHHs decreased in the non-canonical cysteine mutants, whereas the reduced-state samples exhibited decreased thermal stability, with their affinity remaining almost unchanged regardless of the presence of reducing agents. Molecular dynamics simulations suggested that the decrease in affinity of the mutants resulted from increased flexibility of the CDRs, the disappearance of non-canonical cysteine–antigen interactions, and the perturbation of other antigen-interacting residues caused by mutations. These findings highlight the significance of non-canonical cysteines for the affinity of single-domain antibodies and demonstrate that the mutation of non-canonical cysteines is not equivalent to the disruption of non-canonical disulfide bonds with a reducing agent when assessing the function of non-canonical disulfide bonds. [ABSTRACT FROM AUTHOR]

Published
2024
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3. Organoiridium Photosensitizers Induce Specific Oxidative Attack on Proteins within Cancer Cells

Author

Zhang, Pingyu, Chiu, Cookson K. C., Huang, Huaiyi, Lam, Yuko P. Y., Habtemariam, Abraha, Malcomson, Thomas, Paterson, Martin J., Clarkson, Guy J., O'Connor, Peter B., Chao, Hui, Sadler, Peter J., Zhang, Pingyu, Chiu, Cookson K. C., Huang, Huaiyi, Lam, Yuko P. Y., Habtemariam, Abraha, Malcomson, Thomas, Paterson, Martin J., Clarkson, Guy J., O'Connor, Peter B., Chao, Hui, and Sadler, Peter J.

Abstract

Strongly luminescent iridium(III) complexes, [Ir(C,N)2(S ,S )]+ (1 ) and [Ir(C,N)2(O,O)] (2 ), containing C,N (phenylquinoline), O,O (diketonate), or S,S (dithione) chelating ligands, have been characterized by X‐ray crystallography and DFT calculations. Their long phosphorescence lifetimes in living cancer cells give rise to high quantum yields for the generation of 1O2, with large 2‐photon absorption cross‐sections. 2 is nontoxic to cells, but potently cytotoxic to cancer cells upon brief irradiation with low doses of visible light, and potent at sub‐micromolar doses towards 3D multicellular tumor spheroids with 2‐photon red light. Photoactivation causes oxidative damage to specific histidine residues in the key proteins in aldose reductase and heat‐shock protein‐70 within living cancer cells. The oxidative stress induced by iridium photosensitizers during photoactivation can increase the levels of enzymes involved in the glycolytic pathway.

Published
2017

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