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Unraveling DPP4 Receptor Interactions with SARS-CoV-2 Variants and MERS-CoV: Insights into Pulmonary Disorders via
Arpan Narayan Roy1, Aayatti Mallick Gupta2, Deboshmita Banerjee1
1National Institute of Biomedical Genomics, Kalyani 741251, West Bengal, India.
Abstract:
Human coronaviruses like MERS CoV are known to utilize dipeptidyl peptidase 4 (DPP4), apart from angiotensin-converting enzyme 2(ACE2) as a potential co-receptor for viral cell entry. DPP4, the ubiquitous membrane-bound aminopeptidase, is closely associated with elevation of disease severity in comorbidities. In SARS-CoV-2, there is inadequate evidence for combination of spike protein variants with DPP4, and underlying adversity in COVID-19. To elucidate this mechanistic basis, we have investigated interaction of spike protein variants with DPP4 through molecular docking and simulation studies. The possible binding interactions between the receptor binding domain (RBD) of different spike variants of SARS-CoV-2 and DPP4 have been compared with interactions observed in the experimentally determined structure of the complex of MERS-CoV with DPP4. Comparative binding affinity confers that Delta-CoV-2: DPP4 shows close proximity with MERS-CoV:DPP4, as depicted from accessible surface area, radius of gyration and number of hydrogen bonding in the interface. Mutations in the delta variant, L452R and T478K directly participate in DPP4 interaction, enhancing DPP4 binding. E484K in alpha and gamma variants of spike protein is also found to interact with DPP4. Hence, DPP4 interaction with spike protein becomes more suitable due to mutation, especially due to L452R, T478K and E484K. Furthermore, perturbation in the nearby residues Y495, Q474 and Y489 is evident due to L452R, T478K and E484K, respectively. Virulent strains of spike protein are more susceptible to DPP4 interaction and are prone to be victimized in patients due to comorbidities. Our results will aid the rational optimization of DPP4 as a potential therapeutic target to manage COVID-19 disease severity.
Insights
Human coronaviruses use dipeptidyl peptidase 4 (DPP4) for cell entry. SARS-CoV-2 variants, particularly Delta, show enhanced binding to DPP4 due to specific mutations, suggesting DPP4 as a therapeutic target for COVID-19.
Area of Science:
- Virology
- Biochemistry
- Molecular Biology
Background:
- Human coronaviruses, including MERS-CoV, utilize dipeptidyl peptidase 4 (DPP4) as a co-receptor for viral entry, distinct from ACE2.
- DPP4 is linked to increased disease severity in patients with comorbidities.
- Limited evidence exists regarding SARS-CoV-2 spike protein variants interacting with DPP4 and its role in COVID-19 pathogenesis.
Purpose of the Study:
- To investigate the mechanistic basis of interaction between SARS-CoV-2 spike protein variants and DPP4.
- To compare the binding interactions of different spike variants with DPP4 against the MERS-CoV:DPP4 complex.
- To elucidate the role of specific mutations in enhancing DPP4 binding and potential implications for COVID-19 severity.
Main Methods:
- Molecular docking and simulation studies were employed to analyze binding interactions.
- Comparative analysis of binding affinity between SARS-CoV-2 spike variants (Delta, Alpha, Gamma) and DPP4.
- Evaluation of interactions against the experimentally determined structure of MERS-CoV:DPP4 complex.
Main Results:
- The Delta variant's spike protein (Delta-CoV-2) demonstrated binding proximity to DPP4, similar to MERS-CoV:DPP4.
- Specific mutations in the Delta variant (L452R, T478K) and other variants (E484K) were found to directly enhance DPP4 binding.
- Perturbations in nearby spike protein residues were observed due to these key mutations, influencing binding dynamics.
Conclusions:
- DPP4 interaction with the SARS-CoV-2 spike protein is facilitated by specific mutations, particularly L452R, T478K, and E484K.
- Virulent spike protein strains exhibit increased susceptibility to DPP4 interaction, potentially exacerbating disease in patients with comorbidities.
- Targeting DPP4 presents a rational therapeutic strategy for managing COVID-19 disease severity.
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