Success Stories // 19.05.2022 // DECTRIS

Dr. Na Li Wins DECTRIS Award 2022 for Her Work on BioSAXS

A 5-minute read

At Shanghai Synchrotron Radiation Facility (SSRF), Dr. Na Li works on improving Small Angle Scattering (SAS) for biological materials. As a beamline scientist and a group leader, she is addressing these challenges from many perspectives: designing the hardware and software of the beamline, applying the research for drug development, and keeping a great collaborative spirit. In the short-term, she is planning to use the DECTRIS Award to attend the small angle scattering conference, but she also has exciting future projects. In this article, Na opens the virtual doors to her beamline and the exciting world of BioSAXS.

Dr. Na Li, the beamline scientist and group leader of biological Small-Angle X-ray Scattering (BioSAXS) beamline at the Shanghai Synchrotron, is focused on drug development.

Small Angle Scattering for characterization of soft systems 

Solution Small-Angle Scattering (SAS) is a powerful tool for elucidating structural properties of soft matter systems. Material’s properties can be determined at a wide spatial scale (from a few Ångstroms to hundreds of nanometers) and also at wide time scales (milliseconds to several minutes). In recent years, solution SAS has been applied in several research fields, especially in structural biology and in drug discoveries. A great potential to cover different soft-matter systems and processes (e. g. probing the kinetic of self-assembly) was unlocked by advancements in the high throughput and fast time resolution offered by Small-Angle X-ray Scattering (SAXS) as well as by penetrating ability in Small-Angle Neutron Scattering (SANS). 
Together with her colleagues, Dr. Na Li, the beamline scientist and group leader of biological Small-Angle X-ray Scattering (BioSAXS) beamline BL19U2 at Shanghai Synchrotron Radiation Facility (SSRF), performed a comprehensive upgrade on the beamline in the past 5 years to meet the challenges of drug development. The upgrade of optics, electronics, sample environments and scattering data acquisition systems, is devoted exclusively to the requirements of structural biology for drug discoveries. Meanwhile, Na Li is devoted to exploring the potential applications of SAXS in drug development, especially in drug formulation and drug assembly dynamics. “The future for drug discovery will rely more on the protein dynamics. The combination of synchrotron and PILATUS3 X / EIGER2 detectors will facilitate rapid data collections, therefore the unique and rapid temporal structure characterization from SAXS can contribute to shorter time-to-market and a better understanding of structural properties for new drugs and vaccines development”, says Dr. Na Li.

BioSAXs beamline at the Shanghai Synchrotron Radiation Facility features a Wide Angle X-ray Scattering setup (right) with a PILATUS 300K, and Small Angle X-ray Scattering setup (left) with a PILATUS 2M.

With the DECTRIS Award,Dr. Na Li is planning  to participate in the SAS2022 conference in Brazil, where she will present her recent work on the structural characterization of peptide drug assembly and lipid nanoparticles (LNPs) using the solution SAXS. 

Structural characterization of peptide drug assembly and lipid nanoparticles (LNPs) using the solution SAXS

Targeted therapies for melanoma are of urgent need considering the resistance of this aggressive type of cancer to chemotherapeutics. The VDAC1-HK-Ⅱ complex is an emerging target for novel anti-cancer therapies based on induced mitochondria-mediated apoptosis. However, low cell permeability of anti-cancer active peptide fragment pVDAC derived from N-terminal 12-mer peptide fragment of the VDAC1 protein impedes the intracellular targeting, which is likely due to its low net charge and poor hydrophobicity. “The clinical application of peptide therapeutics has been hampered by their poor stability and short half-life in the circulation. Among a variety of peptide drug discovery strategies, peptide self-assembly with amphiphilic compounds is quite promising.” Dr. Na Li said.

For this reason, Dr. Na Li, in collaboration with Prof. Aihua Zou from Shanghai Normal University proposed several self-assembly strategies (e. g. novel multi-block VDAC1-derived cationic amphiphilic peptides) and exploited the designed amphiphilic peptides. In general, the peptide self-assembly process is driven by various weak interactions between the molecules including hydrogen bonding, electrostatic, hydrophobic, π-π and van der Waals interactions. Various types of nanostructures formed by amphiphilic peptides, such as nanovesicles, nanofibers, and nanotubes, may affect the outcome of the biological experiments with amphiphilic peptides. Therefore, proper characterization of the specific structures of designed peptides is important to advance anti-cancer nanomedicine. Synchrotron BioSAXS is a powerful tool to characterize the microstructure of peptide self-assembly with high-throughput screening capabilities. Dr. Na Li and her collaborator developed a theoretical model to fit the experimental scattering from self-assembled peptides and the fitting results can provide guidance for the peptide drug formulations. It should be noted that the scattering results are consistent with that obtained by a cryo-transmitted electron microscope (cryoTEM). As these amphiphilic peptides are designed to amplify cancer cell apoptosis based on disruption of the VDAC1-HK-II contacts at the outer mitochondrial membrane, several bioassays were also performed in order to assess the mitochondria-mediated apoptosis process that can be triggered upon dissociation of the VDAC1-HK-II complex and proved the potential of designed peptides for an efficient melanoma inhibition. 

Proposed model of mitochondrial VDAC1-derived amphiphilic peptides action. Once in the cytosol, Pal-pFL-pVDAC-TAT peptides target mitochondrial membrane, where it can detach HK-Ⅱ from VDAC1 in outer mitochondrial membrane. The disruption of the VDAC1-HK-Ⅱ interaction leads to the decrease of the mitochondrial membrane potential, cytochrome c release and the increased expression level of Bax, cleaved caspase 3 and cleaved caspase 9 proteins, and, finally, apoptosis. Action model of Pal-pVDAC-TAT and pFL-pVDAC-TAT peptides are the same as Pal-pFL-pVDAC-TAT peptide.

The PILATUS3 X-2M detector used in this work is supported by the Research & Development project of the Shanghai Science Center (Y92G031222). The awarded work has been published earlier in ACS Appl. Mater. Interfaces. Further information can be found in references. 

[1] Liu D. et al. (2019) Self-assembly of mitochondria-specific peptide amphiphiles amplifying lung cancer cell death through targeting the VDAC1-hexokinase-II complex, J. Mater. Chem. B7(30), 4706-4716. 
[2] Zhang F. et al. (2021) Mitochondrial voltage-dependent anion channel 1 (VDAC1)-hexokinase-II (HK-II) complex targeted strategy for melanoma inhibition using designed multi-block peptide amphiphiles. ACS Applied Materials & Interfaces, 13(30),  35281-35293.
[3] Liu, G. et al. (2018) Upgraded SSRF BL19U2 beamline for small-angle X-ray scattering of biological macromolecules in solution. J. Appl. Crystal. 51, 1633~1640
[4] Yiwen L. (2020) BL19U2: A small-angle X-ray scattering beamline for biological macromolecules in solution at SSRF. Nucl. Sci. Tech., 31,117,
[5] Hongjin W. (2020) et al. SAS-cam, a program for automatic processing and analysis of small-angle scattering data. J. Appl. Crystal., 53, 1147~1153

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