Influence of Essential Amino Acids on the Synthesis of Polyproteins of the SARS-CoV-2 Virus in the COVID-19 Pathogenesis

Introduction. Diet is a critical factor in the development of viral pathogenesis. Previously it was shown that a high intake of animal proteins correlated directly with dangerous outcomes of SARS-CoV-2 infection. It is necessary to analyze the biochemistry of the metabolic relations of the host and pathogen to explain the contribution of proteins in the development of COVID-19.
Purpose. Identify a risk factor influencing the development of the COVID-19 disease. Compare the amino acid composition of animal and plant proteins with non-structural polyproteins of the SARS-CoV-2 virus. Analyze the impact of dietary essential amino acids (EAAs) in the COVID-19 infectious disease.
Materials and Methods. The scientific data and information needed for this analysis were found in publications and media available on the Internet, as well as taken from statistical databases. Statistical samples were formed from sources and facts available on the Internet. Amino acid sequences of proteins were obtained from databases (https://www.ncbi.nlm.nih.gov/, https://www.uniprot.org/uniprot/).
Results and Discussion. Analysis of statistical data and assessment of nutritional factors during the development of the 22-month pandemic in 20 countries indicated that the outcomes of COVID-19 disease were worsened by excessive consumption of animal proteins. The numbers of reported cases of SARS-CoV-2 virus (RPr) infection and deaths (IFR) from the COVID-19 disease per one thousand inhabitants were significantly lower in regions that predominantly consumed plant-based foods with minimal EAAs. A positive relationship was found between the pathogenicity of SARS-CoV-2 and the amount of animal protein ingested, with correlation coefficients r = 0.83 for RPr and r = 0.61 for IFR. Human Coronaviruses are composed of higher proportion of EAAs than cellular organisms. Edible plant proteins contain 2-3 times less leucine, lysine, and especially threonine and valine (LKTV) than SARS-CoV-2 polypeptides. Optimal synthesis of the SARS-CoV-2 virus Pp1a and Pp1ab polyproteins requires a rapidly large amount of these four EAAs.
Conclusions. A deficiency of EAAs, especially free valine, and threonine, could suppress the early translation of SARS-CoV-2 nonstructural polyproteins. It was concluded that a diet low in EAAs and especially LKTV may prevent rapid, highly productive viral replication and pathogenic development of COVID-19

1. References

2. World Health Organization. https://www.who.int

3. COVID-19. https://www.cdc.gov/coronavirus/2019-ncov/ Accessed: 10.09.2021.

4. https://www.worldometers.info Accessed: 31.01.2022

5. Mei M., Tan X. Current Strategies of Antiviral Drug Discovery for COVID-19. Front Mol Biosci. 2021; 8: 671263. doi: 10.3389/fmolb.2021.671263. Accessed: 31.01.2022

6. Yapasert R., Khaw-On P., Banjerdpongchai R. Coronavirus Infection-Associated Cell Death Signaling and Potential Therapeutic Targets. Molecules. 2021; 26(24): 7459. doi:10.3390/molecules26247459 Accessed: 31.01.2022

7. Allard L., Ouedraogo E., Molleville J., et al. Malnutrition: Percentage and Association with Prognosis in Patients Hospitalized for Coronavirus Disease 2019. Nutrients. 2020; 12(12): 3679. https://doi: 10.3390/nu12123679.

8. Bedock D., Couffignal J., Bel Lassen P., et al. Evolution of Nutritional Status after Early Nutritional Management in COVID-19 Hospitalized Patients. Nutrients. 2021; 13: 2276. https:// doi.org/10.3390/nu13072276

9. Clemente-Suárez V.J., Ramos-Campo D.J., Mielgo-Ayuso J., et al. Nutrition in the Actual COVID-19 Pandemic. A Narrative Review. Nutrients. 2021; 13: 1924. https://doi.org/10.3390/ nu13061924

10. James P.T., Ali Z., Armitage A.E., et al. The Role of Nutrition in COVID-19 Susceptibility and Severity of Disease: A Systematic Review. J Nutr. 2021; 151(7): 1854-1878. doi: 10.1093/jn/nxab059. Accessed: 20.08.2021

11. Mentella M.C., Scaldaferri F., Gasbarrini A., Miggiano G.A.D. The Role of Nutrition in the COVID-19 Pandemic. Nutrients. 2021; 13: 1093. https://doi.org/10.3390/nu13041093

12. Mechanick J.I., Carbone S., Dickerson R.N., et al. Clinical Nutrition Research and the COVID-19 Pandemic: A Scoping Review of the ASPEN COVID-19 Task Force on Nutrition Research. J Parenter Enteral Nutr. 2021; 45(1): 13-31. doi:10.1002/jpen.2036

13. Morais A., Aquino J. S., da Silva-Maia J. K., et al. Nutritional status, diet and viral respiratory infections: perspectives for severe acute respiratory syndrome coronavirus 2. British J.Nutrition. 2021; 125(8): 851–862. https://doi.org/10.1017/S0007114520003311

14. Mortaz E., Bezemer G., Alipoor S.D., et al. Nutritional Impact and Its Potential Consequences on COVID-19 Severity. Front. Nutr. 2021; 8:698617. doi:10.3389/fnut.2021.698617 Accessed: 20.08.2021

15. Ponomarenko S.V. Statistical Analysis of Critical Socioeconomic Factors in the Development of COVID-19 Disease. Voprosy statistiki. 2023; 30(1): 90-100. https://doi.org/10.34023/2313-6383-2023-30-1-90-100 Accessed: 15.02.2023

16. Ponomarenko S.V. Dietary factors influencing the COVID-19 epidemic process. FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology. 2022; 15 (4): 463–471. https://doi.org/10.17749/2070-4909/farmakoekonomika.2022.135.

17. Accessed: 31.01.2023

18. Wu G. Dietary protein intake and human health. Food Funct. 2016; 7, 1251–1265

19. Kim H., Rebholz C.M., Hegde S., et al. Plant-based diets, pescatarian diets and COVID-19 severity: a population-based case–control study in six countries. BMJ Nutrition, Prevention & Health. 2021; doi:10.1136/bmjnph-2021-000272 Accessed: 20.08.2021

20. Aller S., Scott A., Sarkar-Tyson M., Soyer O.S. Integrated human virus metabolic stoichiometric modelling predicts host-based antiviral targets against Chikungunya, Dengue and Zika viruses. J. R. Soc. Interface. 2018; 15: 20180125. http://dx.doi.org/10.1098/rsif.2018.0125

21. Bojkova D., Klann K., Koch B., et al. Proteomics of SARS-CoV-2-infected host cells reveals therapy targets. Nature. 2020; 583(7816): 469-472. doi: 10.1038/s41586-020-2332-7.

22. Delattre H., Sasidharan K., Soyer O.S. Metabolic inhibition of SARS-CoV-2. Life Science Alliance. 2020, 4 (1) e202000869; DOI: 10.26508/lsa.202000869 Accessed:11.11.2021

23. Mussap M., Fanos V. Could metabolomics drive the fate of COVID-19 pandemic? A narrative review on lights and shadows. CCLM. 2021, pp. 000010151520210414. https://doi.org/10.1515/cclm-2021-0414

24. Páez-Franco J.C., Torres-Ruiz J., Sosa-Hernández V.A. et al. Metabolomics analysis reveals a modified amino acid metabolism that correlates with altered oxygen homeostasis in COVID-19 patients. Sci Rep. 2021; 11, 6350. https://doi.org/10.1038/s41598-021-85788-0

25. Wu J, Zhao M, Li C, Zhang Y, Wang DW. The SARS-CoV-2 induced targeted amino acid profiling in patients at hospitalized and convalescent stage. Biosci Rep. 2021; 41(3): BSR20204201. doi: 10.1042/BSR20204201.

26. Cheemarla N.R., Watkins T.A., Mihaylova V.T., et al. Dynamic innate immune response determines susceptibility to SARS-CoV-2 infection and early replication kinetics. J Exp Med. 2021; 218 (8): e20210583. https://doi.org/10.1084/jem.20210583

27. Pyke A.T., Nair N., van den Hurk A.F., et al. Replication Kinetics of B.1.351 and B.1.1.7 SARS-CoV-2 Variants of Concern Including Assessment of a B.1.1.7 Mutant Carrying a Defective ORF7a Gene. Viruses. 2021; 7; 13(6):1087. doi: 10.3390/v13061087.

28. Abdelrahman Z., Li M., Wang X. Comparative Review of SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza A Respiratory Viruses. Front. Immunol. 2020; 11: 552909. doi: 10.3389/fimmu.2020.552909 Accessed: 20.08.2021

29. Hu B., Guo H., Zhou P. et al. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol. 2021; 19: 141–154. https://doi.org/10.1038/s41579-020-00459-7

30. To K. K., Sridhar S., Chiu K. H., et al. Lessons learned 1 year after SARS-CoV-2 emergence leading to COVID-19 pandemic. Emerging microbes & infections. 2021; 10(1): 507–535. https://doi.org/10.1080/22221751.2021.1898291

31. V’kovski, P., Kratzel, A., Steiner, S. et al. Coronavirus biology and replication: implications for SARS-CoV-2. Nat Rev Microbiol. 2021; 19: 155–170. https://doi.org/10.1038/s41579-020-00468-6

32. Yadav R., Chaudhary J.K., Jain N. et al. Role of Structural and Non-Structural Proteins and Therapeutic Targets of SARS-CoV-2 for COVID-19. Cells. 2021; 10(4): 821. doi: 10.3390/cells10040821.

33. Yoshimoto F.K. The Proteins of Severe Acute Respiratory Syndrome Coronavirus‑2 (SARS CoV‑2 or n‑COV19), the Cause of COVID‑19. Protein Journal. 2020; 39:198–216 https://doi.org/10.1007/s10930-020-09901-4

34. https://www.ncbi.nlm.nih.gov/

35. https://www.uniprot.org/uniprot/

36. Finkel Y., Gluck A., Nachshon A. et al. SARS-CoV-2 uses a multipronged strategy to impede host protein synthesis. Nature. 2021; 594, 240–245. https://doi.org/10.1038/s41586-021-03610-3

37. Bhatt P.R., Scaiola A., Loughran G., et al. Structural basis of ribosomal frameshifting during translation of the SARS-CoV-2 RNA genome. SCIENCE. 2021; 372; 6548, 1306-1313. DOI: 10.1126/science.abf3546

38. Bar-On Y.M., Flamholz A., Phillips R., Milo R. SARS-CoV-2 (COVID-19) by the numbers. eLife. 2020; 9, e57309.

39. Joint WHO/FAO/UNU Expert Consultation. Protein and amino acid requirements in human nutrition. World Health Organ Tech Rep Ser. 2007; 935: 1-265 p.

40. https://ourworldindata.org Accessed: 20.07.2021.

41. New Food Balances. Available at: https://FAO.org/faostat/en/#data/FBS Accessed: 20.07.2021

42. Gardner C.D., Jennifer C Hartle J.C., et al. Maximizing the intersection of human health and the health of the environment with regard to the amount and type of protein produced and consumed in the United States, Nutrition Reviews. 2019; 77; 4, 197–215 https://doi.org/10.1093/nutrit/nuy073

43. Gorissen S.H.M., Crombag J.J.R., Senden J.M.G. et al. Protein content and amino acid composition of commercially available plant-based protein isolates. Amino Acids. 2018; 50, 1685–1695. https://doi.org/10.1007/s00726-018-2640-5

44. Kang J.-S. Dietary restriction of amino acids for Cancer therapy. Nutrition & Metabolism. 2020; 17:20 https://doi.org/10.1186/s12986-020-00439-x

45. Verzola D., Picciotto D., Saio M., et al. Low Protein Diets and Plant-Based Low Protein Diets: Do They Meet Protein Requirements of Patients with Chronic Kidney Disease? Nutrients. 2021; 13: 83. https://doi.org/10.3390/nu13010083

46. Paul C., Leser S., Oesser S. Significant Amounts of Functional Collagen Peptides Can Be Incorporated in the Diet While Maintaining Indispensable Amino Acid Balance. Nutrients. 2019; 11; 5, 1079; https://doi.org/10.3390/nu11051079

47. Schmidt J., Rinaldi S., Scalbert A. et al. Plasma concentrations and intakes of amino acids in male meat-eaters, fish-eaters, vegetarians and vegans: a cross-sectional analysis in the EPIC-Oxford cohort. Eur J Clin Nutr. 2016; 70, 306–312. https://doi.org/10.1038/ejcn.2015.144

48. Mariotti F., Gardner C.D. Dietary Protein and Amino Acids in Vegetarian Diets-A Review. Nutrients. 2019; 11; 11: 2661. doi:10.3390/nu11112661 Accessed: 07.10.2021

49. Bröer S., Bröer A. Amino acid homeostasis and signaling in mammalian cells and organisms. Biochem J. 2017; 474; 12: 1935–1963. https://doi.org/10.1042/BCJ20160822

50. Groen B.B.L., Horstman A.M., Hamer H.M., et al. Post-Prandial Protein Handling: You Are What You Just Ate. PLoS ONE. 2015; 10; 11: e0141582.

51. doi:10.1371/ journal.pone.0141582

52. Horstman A.M.H., Ganzevles R.A., Kudla U., et al. Postprandial blood amino acid concentrations in older adults after consumption of dairy products: The role of the dairy matrix. https://doi.org/10.1016/j.idairyj.2020.104890

53. Trommelen J., Tome D., van Loon L. C. Gut amino acid absorption in humans: Concepts and relevance for postprandial metabolism. Clinical Nutrition Open Science 2021; 36: 43e55 DOI: https://doi.org/10.1016/j.nutos.2020.12.006

54. Atila A., Alay H., Yaman M.E. et al. The serum amino acid profile in COVID-19. Amino Acids. 2021. https://doi.org/10.1007/s00726-021-03081-w Accessed: 10.01.2022

55. Holeček M. The role of skeletal muscle in the pathogenesis of altered concentrations of branched-chain amino acids (valine, leucine, and isoleucine) in liver cirrhosis, diabetes, and other diseases. Physiol Res. 2021; 70; 3: 293-305. doi: 10.33549/physiolres.934648.

56. Yamamoto H, Kondo K., Tanaka T., et al. Reference intervals for plasma-free amino acid in a Japanese population. Ann. Clin. Biochemistry. 2016; 53; 3: 357–364

57. Ren W., Rajendran R., Zhao Y., et al. Amino Acids As Mediators of Metabolic Cross Talk between Host and Pathogen. Front. Immunol. 2018; 9:319. doi:10.3389/fimmu.2018.00319

58. Purpura M., Lowery R.P., Joy J.M., et al. A Comparison of Blood Amino Acid Concentrations Following Ingestion of Rice and Whey Protein Isolate: A Double-Blind Crossover Study. J Nutr Health Sci. 2014; 1; 3: 306

59. Sans M.D., Crozier S.J., Vogel N.L. Dietary Protein and Amino Acid Deficiency Inhibit Pancreatic Digestive Enzyme mRNA Translation by Multiple Mechanisms. Cell Mol Gastroenterol Hepatol. 2021; 11; 1: 99-115. doi: 10.1016/j.jcmgh.2020.07.008.

60. Wilkinson D.J., Bukhari S.S.I., Phillips B.E., et al. Effects of leucine-enriched essential amino acid and whey protein bolus dosing upon skeletal muscle protein synthesis at rest and after exercise in older women. Clin Nutr. 2018; 37(6 Pt A):2011-2021. doi: 10.1016/j.clnu.2017.09.008.

61. Yang Y., Churchward-Venne T.A., Burd N. A., et al. Myofibrillar protein synthesis following ingestion of soy protein isolate at rest and after resistance exercise in elderly men. Nutrition & Metabolism. 2012; 9:57. 10.1113/jphysiol.2003.050674.

62. Bohé J., Low A., Wolfe R.R., et al. Human muscle protein synthesis is modulated by extracellular, not intramuscular amino acid availability: a dose-response study. J Physiol. 2003; 552(Pt 1): 315-24. doi: http://www.nutritionandmetabolism.com/content/9/1/57

63. Banerjee A.K., Blanco M.R., Bruce E.A., et al. SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses. Cell. 2020; 183(5): 1325-1339.e21. doi: 10.1016/j.cell.2020.10.004.

64. Shi D, Yan R, Lv L, et al. The serum metabolome of COVID-19 patients is distinctive and predictive. Metabolism. 2021;118:154739. doi:10.1016/j.metabol.2021.154739

65. Rees C.A., Rostad C.A., Mantus G. et al. Altered amino acid profile in patients with SARS-CoV-2 infection. Proc Natl Acad Sci USA. 2021; 118: 25 e2101708118; DOI: 10.1073/pnas.2101708118 Accessed:11.11.2021

66. Bart van Sloun B., Goossens G.H., Erdos B., et al. The Impact of Amino Acids on Postprandial Glucose and Insulin Kinetics in Humans: A Quantitative Overview. Nutrients. 2020; 12, 3211; doi:10.3390/nu12103211

67. Renz A., Widerspick L., Dräger A. Genome-Scale Metabolic Model of Infection with SARS-CoV-2 Mutants Confirms Guanylate Kinase as Robust Potential Antiviral Target. Genes (Basel). 2021; 12(6): 796. doi: 10.3390/genes12060796.

68. Renz A., Widerspick L., Dräger A. FBA reveals guanylate kinase as a potential target for antiviral therapies against SARS-CoV-2. Bioinformatics. 2020; 36, Issue Supplement_2, Pages i813–i821, https://doi.org/10.1093/bioinformatics/btaa813

69. Mazor K.M., Dong L., Mao Y., et al. Effects of single amino acid deficiency on mRNA translation are markedly different for methionine versus leucine. Scientific Report. 2018; 8:8076 | DOI:10.1038/s41598-018-26254-2

70. Lapointe C.P., Grosely R., Johnson A.G., et al. Dynamic competition between SARS-CoV-2 NSP1 and mRNA on the human ribosome inhibits translation initiation. Proc Natl Acad Sci USA. 2021; 118(6): e2017715118. doi: 10.1073/pnas.2017715118.

71. Cantwell A.M., Singh H., Platt M., et al. Kinetic multi-omic analysis of responses to SARS-CoV-2 infection in a model of severe COVID-19. J Virol. 2021; 95: e01010-21. https://doi.org/10.1128/JVI.01010-21.

72. Uchiyama T., Fujita T., Gukasyan H.J., et al. Functional characterization and cloning of amino acid transporter B0,+ (ATB0,+) in primary cultured rat pneumocytes. https://doi.org/10.1002/jcp.21254 Accessed: 10.01.2022

73. He X, Hong W, Pan X, Lu G, Wei X. SARS-CoV-2 Omicron variant: Characteristics and prevention. MedComm. 2021; 2(4):838–45. doi: 10.1002/mco2.110. Accessed: 10.01.2022

74. Bergström J., Fürst P., Norée L.O., Vinnars E. Intracellular free amino acid concentration in human muscle tissue. J. Appl. Physiol. 1974; 36, 693–697 PMID:4829908,

75. Hoffmann E.K., Lambert I.H. Amino acid transport and cell volume regulation in Ehrlich ascites tumour cells. J. Physiol. 1983; 338, 613–625 doi:10.1113/jphysiol.1983.sp014692

76. Fehrenbach H. Alveolar epithelial type II cell: defender of the alveolus revisited. BioMed Central Ltd (Print ISSN 1465-9921. 2001; Available online http://respiratory-research.com/content/2/1/033 Accessed: 10.01.2022

77. Knudsen, L., Ochs, M. The micromechanics of lung alveoli: structure and function of surfactant and tissue components. Histochem Cell Biol 150, 661–676 (2018). https://doi.org/10.1007/s00418-018-1747-9

78. Mason R.J. Biology of alveolar type II cells. Respirology. 2006; 11: S12–S15 https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1440-1843.2006.00800.x Accessed: 30.11.2021

79. Weibel E.R. On the Tricks Alveolar Epithelial Cells Play to Make a Good Lung. Am J Respir Crit Care Med. 2015; 191; 5: 504–513, https://www.atsjournals.org/doi/pdf/10.1164/rccm. 201409-1663OE Accessed: 30.11.2021

80. Srikanth S., Chen Z. Plant Protease Inhibitors in Therapeutics-Focus on Cancer Therapy. Front. Pharmacol. 2016; 7; 470: 1-19. https://www.frontiersin.org/article/10.3389/fphar.2016.00470

81. Billinger E., Zuo Sh., Johansson G. Characterization of Serine Protease Inhibitor from Solanum tuberosum Conjugated to Soluble Dextran and Particle Carriers. ACS Omega. 2019; 4; 19: 18456–18464 https://doi.org/10.1021/acsomega.9b02815

82. Komarnytsky S., Cook A., Raskin I. Potato protease inhibitors inhibit food intake and increase circulating cholecystokinin levels by a trypsin-dependent mechanism. Int J Obes (Lond). 2011; 35(2): 236-243. doi: 10.1038/ijo.2010.192.

83. Wamai, R.G., Hirsch, J.L., Van Damme, W., et al. What Could Explain the Lower COVID-19 Burden in Africa Despite Considerable Circulation of the SARS-CoV-2 Virus?. Preprints 2021, 2021050549 doi: 10.20944/preprints202105.0549.v1. Accessed: 20.08.2021