Receptor Binding for the Entry Mechanisms of SARS-CoV-2: Insights from the Original Strain and Emerging Variants

Mahdi, Mohamed; Kiarie, Irene Wanjiru; Mótyán, János András; Hoffka, Gyula; Al-Muffti, Aya Shamal; Tóth, Attila; Tőzsér, József

doi:10.3390/v17050691

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Receptor Binding for the Entry Mechanisms of SARS-CoV-2: Insights from the Original Strain and Emerging Variants

by

Mohamed Mahdi

^1,2,*

,

Irene Wanjiru Kiarie

^1,3,

János András Mótyán

¹

,

Gyula Hoffka

^1,4

,

Aya Shamal Al-Muffti

^1,3,

Attila Tóth

⁵

and

József Tőzsér

^1,*

¹

Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary

²

Department of Infectology, Faculty of Medicine, University of Debrecen, 4031 Debrecen, Hungary

³

Doctoral School of Molecular Cellular and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary

⁴

Department of Chemistry, Lund University, Box 124, 221 00 Lund, Sweden

⁵

Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary

^*

Authors to whom correspondence should be addressed.

Viruses 2025, 17(5), 691; https://doi.org/10.3390/v17050691 (registering DOI)

Submission received: 3 April 2025 / Revised: 3 May 2025 / Accepted: 8 May 2025 / Published: 10 May 2025

(This article belongs to the Special Issue Mechanism of Receptor Recognition in Coronavirus, 2nd Edition)

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Abstract

Since its emergence in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continuously evolved, giving rise to multiple variants that have significantly altered the trajectory of the COVID-19 pandemic. These variants have resulted in multiple waves of the pandemic, exhibiting characteristic mutations in the spike (S) protein that may have affected receptor interaction, tissue tropism, and cell entry mechanisms. While the virus was shown to primarily utilize the angiotensin-converting enzyme 2 (ACE2) receptor and host proteases such as transmembrane serine protease 2 (TMPRSS2) for entry into host cells, alterations in the S protein have resulted in changes to receptor binding affinity and use of alternative receptors, potentially expanding the virus’s ability to infect different cell types or tissues, contributing to shifts in clinical presentation. These changes have been linked to variations in disease severity, the emergence of new clinical manifestations, and altered transmission dynamics. In this paper, we overview the evolving receptor utilization strategies of SARS-CoV-2, focusing on how mutations in the S protein may have influenced viral entry mechanisms and clinical outcomes across the ongoing pandemic waves.

Keywords: coronaviruses; SARS-CoV-2; viral entry; receptor utilization; COVID-19

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MDPI and ACS Style

Mahdi, M.; Kiarie, I.W.; Mótyán, J.A.; Hoffka, G.; Al-Muffti, A.S.; Tóth, A.; Tőzsér, J. Receptor Binding for the Entry Mechanisms of SARS-CoV-2: Insights from the Original Strain and Emerging Variants. Viruses 2025, 17, 691. https://doi.org/10.3390/v17050691

AMA Style

Mahdi M, Kiarie IW, Mótyán JA, Hoffka G, Al-Muffti AS, Tóth A, Tőzsér J. Receptor Binding for the Entry Mechanisms of SARS-CoV-2: Insights from the Original Strain and Emerging Variants. Viruses. 2025; 17(5):691. https://doi.org/10.3390/v17050691

Chicago/Turabian Style

Mahdi, Mohamed, Irene Wanjiru Kiarie, János András Mótyán, Gyula Hoffka, Aya Shamal Al-Muffti, Attila Tóth, and József Tőzsér. 2025. "Receptor Binding for the Entry Mechanisms of SARS-CoV-2: Insights from the Original Strain and Emerging Variants" Viruses 17, no. 5: 691. https://doi.org/10.3390/v17050691

APA Style

Mahdi, M., Kiarie, I. W., Mótyán, J. A., Hoffka, G., Al-Muffti, A. S., Tóth, A., & Tőzsér, J. (2025). Receptor Binding for the Entry Mechanisms of SARS-CoV-2: Insights from the Original Strain and Emerging Variants. Viruses, 17(5), 691. https://doi.org/10.3390/v17050691

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Receptor Binding for the Entry Mechanisms of SARS-CoV-2: Insights from the Original Strain and Emerging Variants

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