Abstract
The novel coronavirus SARS-CoV-2 has caused a pandemic resulting in millions of deaths worldwide. While multiple vaccines have been developed, insufficient vaccination combined with adaptive mutations create uncertainty for the future. Here, we discuss novel strategies to control COVID-19 relying on Defective Interfering Particles (DIPs) and related particles that arise naturally during an infection. Our intention is to encourage and to provide the basis for the implementation of such strategies by multi-disciplinary teams. We therefore provide an overview of SARS-CoV-2 for a multi-disciplinary readership that is specifically tailored to these strategies, we identify potential targets based on the current knowledge of the properties and functions of coronaviruses, and we propose specific strategies to engineer DIPs and other interfering or therapeutic nanoparticles.
Highlights
In a Holliday lecture in 1999, Don Ganem explained that pandemic infection is a recurrent, not a temporary, phenomenon: “The supervention of the AIDS pandemic put the lie to all of these optimistic predictions about how infectious disease was conquered and was no longer a problem
A synthetic defective interfering SARS-CoV-2 was developed using the 5 UTR and the adjacent 5 part of nsp1 in ORF1a, the nsp15 that includes the putative packaging signal and the sequence spanning the 3 part of the N sequence, ORF10 and the 3 -UTR. The rationale of this design is that a long ORF enables defective interfering genomes in some CoVs to replicate more efficiently and, since multiple transcriptional regulatory sequences (TRS) reduce replication efficiency, the 3 portion was chosen to start within the N sequence to exclude its transcription-regulating sequences (TRSs)
One approach relies on the use of Defective Interfering Particles (DIPs) and Therapeutic interfering particles (TIPs) that compete with the wild-type virus for entry, replication, assembly, and egress
Summary
In a Holliday lecture in 1999, Don Ganem explained that pandemic infection is a recurrent, not a temporary, phenomenon: “The supervention of the AIDS pandemic put the lie to all of these optimistic predictions about how infectious disease was conquered and was no longer a problem. Other particles that can be produced during an infection include the virus-like particles (VLPs) These particles are composed of viral structural proteins, they morphologically resemble the parental virus but are non-infectious due to lack of genetic material. Another type is the extracellular vesicle (EV). Packaging of DVGs into viral particles results in DIP production Another particle produced during CoV infections is the VLP. This pairing is induced by the ribonucleoprotein complex proteins, which have been localized to networks of convoluted membranes and vesicles [30] Targeting this network is important because viral polymerases that have a decreased fidelity often have an increased production of defective viral genomes [31,32,33]. Given the potential value of a recombinant protein, it may be worth considering the construction of a TIP to encode fusion of the ACE2 fragment to the M-protein to perturb SARS-CoV-2 assembly
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