Metabolomics and Computational Analysis of the Role of Monoamine Oxidase Activity in Delirium and SARS-COV-2 Infection (preprint)

Delirium is an acute change in attention and cognition occurring in ~65% of severe SARS-CoV-2 cases. It is also common following surgery and an indicator of brain vulnerability and risk for the development of dementia. In this work we analyzed the underlying role of metabolism in delirium-susceptibility in the postoperative setting using metabolomic profiling of cerebrospinal fluid and blood taken from the same patients prior to planned orthopaedic surgery. Distance correlation analysis and Random Forest (RF) feature selection were used to determine changes in metabolic networks. We found significant concentration 2 differences in several amino acids, acylcarnitines and polyamines linking delirium-prone patients to known factors in Alzheimer’s disease such as monoamine oxidase B (MAOB) protein. Subsequent computational structural comparison between MAOB and angiotensin converting enzyme 2 as well as protein-protein docking analysis showed that there potentially is strong binding of SARS-CoV-2 spike protein to MAOB. The possibility that SARS-CoV-2 influences MAOB activity leading to the observed neurological and platelet-based complications of SARS-CoV-2 infection requires further investigation.

Computational identification of human biological processes and protein sequence motifs putatively targeted by SARS-CoV-2 proteins using protein-protein interaction networks (preprint)

While the COVID-19 pandemic is causing important loss of life, knowledge of the effects of the causative SARS-CoV-2 virus on human cells is currently limited. Investigating protein-protein interactions (PPIs) between viral and host proteins can provide a better understanding of the mechanisms exploited by the virus and enable the identification of potential drug targets. We therefore performed an in-depth computational analysis of the interactome of SARS-CoV-2 and human proteins in infected HEK293 cells published by Gordon et al. to reveal processes that are potentially affected by the virus and putative protein binding sites. Specifically, we performed a set of network-based functional and sequence motif enrichment analyses on SARS-CoV-2-interacting human proteins and on a PPI network generated by supplementing viral-host PPIs with known interactions. Using a novel implementation of our GoNet algorithm, we identified 329 Gene Ontology terms for which the SARS-CoV-2-interacting human proteins are significantly clustered in the network. Furthermore, we present a novel protein sequence motif discovery approach, LESMoN-Pro, that identified 9 amino acid motifs for which the associated proteins are clustered in the network. Together, these results provide insights into the processes and sequence motifs that are putatively implicated in SARS-CoV-2 infection and could lead to potential therapeutic targets.

Potential involvement of monoamine oxidase activity in SARS-COV2 infection and delirium onset (preprint)

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of extra-respiratory signs and symptoms. One such manifestation is delirium, an acute confusional state occurring in 60-70% of severe SARS-CoV-2 cases. Delirium is also a common clinical syndrome following planned orthopedic surgery. This investigation initially explored the underlying role of metabolism in delirium-susceptibility in this setting. Metabolomics profiles of cerebrospinal fluid (CSF) and blood taken prior to surgery found significant concentration differences of several amino acids, acylcarnitines and polyamines were observed in delirium-prone patients. Phenethylamine (PEA) concentrations in delirium-prone patients was significantly lower in CSF than in blood, whilst in age- and gender-matched controls the opposite was observed (adjusted p values: 1.8x10-6 (control) and 1.788x10-10 (delirium)). PEA is metabolised by monoamine oxidase B (MAOB), a putative enzyme target for the treatment of Alzheimers disease, Parkinsons disease and depression. Our computational structural comparisons of MAOB and angiotensin converting enzyme (ACE) 2 found high similarity, specifically within the SARS-CoV-2 spike protein. MAOB structural alignment to ACE2 was 51% overall, but this was over 95% in the ACE2-spike protein binding region. Thus, it is possible that the spike protein interacts with MAOB on a molecular level. A previously published metabolomic dataset of control subjects and patients with either mild or severe COVID-19 was then analysed. Major concentration differences in some metabolites attributed to altered MAO activity were detected. Therefore, our hypothesis is that the SARS-CoV-2 influences MAOB activity, which is one potential cause for the many observed neurological and platelet based complications of SARS-CoV-2 infection. Further research is required to establish what effect MAOB inhibitors might have on these pathways. There is no evidence at present to support the withholding of MAOB inhibitors.