The Road Less Traveled: Advancing SARS-CoV-2 research with the exploration of non-structural proteins using organoid models

Until recently, the study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis has primarily focused on surface structural proteins, with non-structural proteins (NSPs) regarded as less important. However, recent findings have shown the critical role of NSP6 in replication organelles, shedding light on these lesser-studied proteins. This paper proposes using organoids to explore NSP functions in SARS Cov-2. The study addresses two main questions: how can organoids be further applied to allow SARS-CoV-2 research advancement with NSPs, and what NSPs of SARS-CoV-2 need further exploration? A systems biology approach is suggested, involving the overexpression of NSPs in cells forming the organoid and analyses using transcription screening, proteomics, and microRNA profiling. Exploring all 16 NSPs using the proposed approach will provide a more robust understanding of SARS-CoV-2 mechanisms and could lead to the development of therapeutic agents. This research also has implications for "long COVID" research, in which various organoids can be used to model changes in different affected organs. Furthermore, it has implications for developing nanoparticles targeting viral or host chaperone proteins. By implementing the proposed approaches, we can move closer to understanding SARS Cov-2 mechanisms and developing a therapeutic that can be used against the virus.