The use of knowledge management tools in viroinformatics. Example study of a highly conserved sequence motif in Nsp3 of SARS-CoV-2 as a therapeutic target

Abstract

Knowledge management tools that assist in systematic review and exploration of scientific knowledge generally are of obvious potential importance in evidence based medicine in general, but also to the design of therapeutics based on the protein subsequences and fold motifs of virus proteins as considered here. Rapid access to bundles (clusters) of related elements of knowledge gathered from diverse sources on the Internet and from growing knowledge repositories seem particularly helpful when exploring less obvious therapeutic targets in viruses (for which knowledge new to the researcher is important), and when using the following concept. Subsequences of amino acid residue sequences of proteins that are conserved across strains and species are (a) more likely to be important targets and (b) less likely to exhibit escape mutations that would make them resistant to vaccines and therapeutic agents. However, the terms “conserved” and even “highly conserved” used by authors are matters of degree, depending on how distant from SARS-CoV-2 they wished to go in comparing other sequences. The binding site to the human ACE2 protein as virus receptor and human antibody CR3022 binding site on the spike glycoprotein are rather variable by the criteria used in the present and preceding studies. To look for more strongly conserved targets, open reading frames of SARS-CoV-2 were examined for extremely highly conserved regions, meaning recognizable across many viruses and organisms. Most prominent is a motif found in SARS-CoV-2 non-structural protein 3 (Nsp3). It relates to a fold called type called the macro domain and has remarkably wide distribution across organisms including humans with significant homologies involving three especially conserved subsequences (a) VVVNAANVYLKHGGGVAGALNK, (b) LHVVGPNVNKG, and (c) PLLSAGIFG. Careful study of the variations of these and of the more variable sequences between and around them might provide a finer “scalpel” to ensure inhibition of a vital function of the virus without impairing the functions of related host macro domains.

Current Updates on Naturally Occurring Compounds Recognizing SARS-CoV-2 Druggable Targets

“…Exploring the possible mechanisms of action involving LF, a computational investigation suggested its possible effect in the early stages of the infection. Indeed, by 2D-Zernike descriptors of molecular surfaces of sialic acid receptors on the host cell membrane, ACE2, S, M, and E proteins, it was highlighted that LF could affect the viral attachment to the host cell due to its probable competition with the virus in the binding to sialic acid [ 61 , 62 , 63 , 64 ]. Additionally, potential competition between ACE2 and LF in the binding site of SARS-CoV-2 Spike was suggested.…”

Potential Achilles heels of SARS-CoV-2 are best displayed by the base order-dependent component of RNA folding energy

“…In previous HIV-1 studies the base differences between just two individual sequences sufficed for the tabulation of a statistically significant set of base substitution frequencies [2]. The lower mutation rates of SARS-CoV-2 strains [11] required the tabulation of changeable positions relative to the prototype (i.e. polymorphisms), among a set of individual sequences in a geographical region.…”

“…The lower mutation rates of SARS-CoV-2 strains (Robson 2020) required the tabulation of changeable positions relative to the prototype (i.e. polymorphisms) among a set of individual sequences in a geographical region.…”

“…We identify certain open reading frames (ORFs) that, because of their conservation, have so far attracted therapeutic interest mainly related to their functions at the protein level (Robson 2020;Issa et al, 2020), rather than at the level of the corresponding, yet highly structured, regions of the genome. The ribosomal frameshift element (FSE) that is among our results, is attracting attention (Haniff et al, 2020;Kelly et al, 2020;Ziv et al, 2020).…”

“…We here report similar highly conserved structural regions of the SARS-CoV-2 genome, one or more of which should be susceptible to targeting [9, 10]. We identify certain open reading frames (ORFs) that, because of their conservation, have so far attracted therapeutic interest mainly related to their functions at the protein level [11, 12], rather than at the level of the corresponding, yet highly structured, regions of the genome. The ribosomal frameshift element (FSE) that is among our results, is attracting attention [10, 13, 14].…”