Host cell glutamine metabolism as a potential antiviral target

Abstract

A virus minimally contains a nucleic acid genome packaged by a protein coat. The genome and capsid together are known as the nucleocapsid, which has an envelope containing a lipid bilayer (mainly phospholipids) originating from host cell membranes. The viral envelope has transmembrane proteins that are usually glycoproteins. The proteins in the envelope bind to host cell receptors, promoting membrane fusion and viral entry into the cell. Virus-infected host cells exhibit marked increases in glutamine utilization and metabolism. Glutamine metabolism generates ATP and precursors for the synthesis of macromolecules to assemble progeny viruses. Some compounds derived from glutamine are used in the synthesis of purines and pyrimidines. These latter compounds are precursors for the synthesis of nucleotides. Inhibitors of glutamine transport and metabolism are potential candidate antiviral drugs. Glutamine is also an essential nutrient for the functions of leukocytes (lymphocyte, macrophage, and neutrophil), including those in virus-infected patients. The increased glutamine requirement for immune cell functions occurs concomitantly with the high glutamine utilization by host cells in virus-infected patients. The development of antiviral drugs that target glutamine metabolism must then be specifically directed at virus-infected host cells to avoid negative effects on immune functions. Therefore, the aim of this review was to describe the landscape of cellular glutamine metabolism to search for potential candidates to inhibit glutamine transport or glutamine metabolism.

Amino acid metabolism and signalling pathways: potential targets in the control of infection and immunity

“…Gln complementation showed antiviral activity against the herpes virus [ 58 , 59 ] and a complement associating zinc, vitamin D and Gln displayed a potential adjuvant and synergistic therapeutic potential in modulating antiviral immune defences functions through γ-IFN signalling in the treatment of COVID‑19 [ 60 ]. However, as virus-infected host cells have an increase in Gln utilisation, development of antiviral strategy targeting Gln must deplete Gln in the environment of virus-infected host cells while favouring Gln utilisation by host immune cell system [ 61 ].…”

Metabolic Perturbation Associated With COVID-19 Disease Severity and SARS-CoV-2 Replication

“…The mild and severe groups were matched by gender (male: 79% vs 91%, p=0.6514), BMI [median (IQR): 29 ( 25 , 26 , 27 , 28 , 29 , 30 , 31 ) vs 28 ( 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ); p=0.8622] and age [median (IQR): 57 (44-63) vs 57 (52-69); p=0.2831]. The HC has significantly lower age [median (IQR): 48 ( 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 )], lower BMI [median (IQR): 24 ( 21 , 22 , 23 , 24 , 25 )] ( Table S3 ). The IgG CoV-2 antibody test showed 10 of the HC were CoV-2 antibody positive (HC-CoV-2 Ab+, Fig S2 ).…”

Antiviral strategies targeting host factors and mechanisms obliging +ssRNA viral pathogens

“… 44 , 45 , 46 , 47 Focussing primarily on +ssRNA viruses, lipid biosynthesis pathway, glycolytic pathway, the stress-granule formation machinery, polyamine metabolism/catabolism, cytokine based inflammatory response, and the proteasome based ubiquitination/deubiquitination steps are the key targets exploited by viruses. 48 , 49 , 50 , 51 , 52 A majority of these factors are dispensable for the host cell but are highly essential for viruses to complete their life cycle.…”