Interaction Analysis of Adenovirus L5 Protein With Pancreatic Cancer Cell Surface Receptor to Analyze Its Affinity for Oncolytic Virus Therapy

Abstract

This study seeks to investigate the interaction profile of the L5 protein of oncolytic adenovirus with the overexpressed surface receptors of pancreatic cancer. This is an important area of research because pancreatic cancer is one of the most fatal malignancies with a very low patient survival rate. Multiple therapies to date to improve the survival rate are reported; however, they show a comparatively low success rate. Among them, oncolytic virus therapy is a type of immunotherapy that is currently under deliberation by researchers for multiple cancer types in various clinical trials. Talimogene laherparepvec (T-VEC) is the first oncolytic virus approved by the US Food and Drug Administration (FDA) for melanoma. The oncolytic virus not only kills cancer cells but also activates the anticancer immune response. Therefore, it is preferred over others to deal with aggressive pancreatic cancer. The efficacy of therapy primarily depends on how effectively the oncolytic virus enters and infects the cancer cell. Cell surface receptors and their interactions with virus coat proteins are a crucial step for oncolytic virus entry and a pivotal determinant. The L5 proteins of the virus coat are the first to interact with host cell surface receptors. Therefore, the objective of this study is to analyze the interaction profile of the L5 protein of oncolytic adenovirus with overexpressed surface receptors of pancreatic cancer. The L5 proteins of three adenovirus serotypes HAdV2, HAdV5, and HAdV3 were utilized in this study. Overexpressed pancreatic cancer receptors include SLC2A1, MET, IL1RAP, NPR3, GABRP, SLC6A6, and TMPRSS4. The protein structures of viral and cancer cell protein were docked using the High Ambiguity Driven protein–protein DOCKing (HADDOCK) server. The binding affinity and interaction profile of viral proteins against all the receptors were analyzed. Results suggest that the HAdV3 L5 protein shows better interaction as compared to HAdV2 and HAdV5 by elucidating high binding affinity with 4 receptors (NPR3, GABRP, SLC6A6, and TMPRSS4). The current study proposed that HAdV5 or HAdV2 virus pseudotyped with the L5 protein of HAdV3 can be able to effectively infect pancreatic cancer cells. Moreover, the current study surmises that the affinity maturation of HAdV3 L5 can enhance virus attachment with all the receptors of cancer cells.

Frontiers and future of immunotherapy for pancreatic cancer: from molecular mechanisms to clinical application

“…As a prominent research direction in the field of pancreatic cancer treatment, immunotherapeutic approaches have included various innovative strategies ( 140 , 141 ). Among these, ACT ( 142 ), oncolytic virus therapy ( 143 ), and matrix depletion therapy ( 144 ) have shown significant therapeutic potential. Although they enhance functioning of the immune system to combat pancreatic cancer via different mechanisms, each therapeutic strategy has its own unique advantages and disadvantages ( Figure 3 ).…”

Development and application of oncolytic viruses as the nemesis of tumor cells

“…Not all viruses are suitable for use as oncolytic viruses, and their selection depends on factors such as the potential pathogenicity, immunogenicity, and genes encoding the therapeutic ability of the virus ( Russell et al, 2012 ). Several oncolytic viruses are currently in use, including adenovirus (Ad; Gállego Pérez-Larraya et al, 2022 ; Nisar et al, 2022 ; Yngve et al, 2022 ), herpes simplex virus (HSV; Kawamura et al, 2022 ; Scanlan et al, 2022 ; Shayan et al, 2022 ), vaccinia virus (VV; Zhou et al, 2020 ; Yang Z. et al, 2021 ), reovirus ( Seyed-Khorrami et al, 2021 ; Yang C. et al, 2021 ), poliovirus ( Ghajar-Rahimi et al, 2022 ; Wei et al, 2022 ), coxsackie virus (CV; Lu et al, 2020 ; Sarwar et al, 2021 ), Newcastle disease virus (NDV; Chan et al, 2021 ), vesicular stomatitis virus (VSV; Sarwar et al, 2021 ), myxoma virus ( Villa et al, 2022 ), and some enteroviruses ( Xu et al, 2021 ; Kolyasnikova et al, 2023 ).…”