In-Silico Evidence for a Two Receptor Based Strategy of SARS-CoV-2

Milanetti, Edoardo; Miotto, Mattia; Rienzo, Lorenzo Di; Nagaraj, Madhu; Monti, Michele; Golbek, Thaddeus W.; Gosti, Giorgio; Roeters, Steven J.; Weidner, Tobias; Otzen, Daniel E.; Ruocco, G.

doi:10.3389/fmolb.2021.690655

Cited by 65 publications

(73 citation statements)

References 71 publications

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“…Emerging evidence also suggest that the CoV-2 potentially uses multiple entry receptors such as the sialic acid receptors and the toll like receptors (TLR) for host cell entry (Vaira et al, 2020;Gadanec et al, 2021). Binding of SARS-CoV-2 to salivary sialic acid could interfere with the glycoproteins mediated transport of tastants and contribute to loss of taste (Milanetti et al, 2021). In-situ models of direct binding of coronavirus spike protein with TLR1, 4 and 6 support the specific roles of these TLRs in CoV-2 entry and COVID-19 (Choudhury and Mukherjee, 2020).…”

Section: Pathogenesis Of Taste Dysfunction In Long Covid-19mentioning

confidence: 99%

Taste Dysfunction and Long COVID-19

Srinivasan

2021

Front. Cell. Infect. Microbiol.

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Chemosensory dysfunctions including anosmia, hyposmia, ageusia, and hypogeusia constitute one of the chief symptoms of SARS-CoV2 infection. Meta-analyses suggest that the prevalence of olfactory dysfunction ranged between 41.0-61.0% and that of gustatory dysfunction between 38.2-49.0% in COVID-19. Indeed, self-reported loss of smell and taste has been observed to be more prognostic than other symptoms including fatigue, fever, or cough in predicting symptomatic infection (Agyeman et al., 2020;Mastrangelo et al., 2021). Significantly, loss of taste is consistently reported as a common symptom of long COVID-19, defined as persistence of symptoms four weeks after infection (Biadsee et al., 2021). Following over four-hundred SARS-CoV-2 infected individuals for severity, improvement, and recovery of subjective chemosensory dysfunction for four months, Schwab et al. have reported that the recovery from loss of taste became stagnant after about two months with little improvement subsequently (Schwab et al., 2021). An overview of emerging research on the pathogenesis of long COVID-19 and an opinion about potential mechanisms for gustatory dysfunction is included below. GUSTATION-THE PROCESS OF TASTE PERCEPTIONGustation is an integrated event of multiple physiological processes occurring concurrently through activation of specialized taste, orosensory, and gastrointestinal fibers (Simon et al., 2006). The taste buds, that constitute the peripheral chemosensory units, are distributed in the papillae of the tongue, palate, larynx, and esophagus. Each taste bud consists of 50-100 tightly packed specialized epithelial cells called taste receptor cells that are of three types. Type-I are glial-like cells, type-II cells express

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Section: Pathogenesis Of Taste Dysfunction In Long Covid-19mentioning

confidence: 99%

Taste Dysfunction and Long COVID-19

Srinivasan

2021

Front. Cell. Infect. Microbiol.

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“…Several in silico structural studies have searched for and analysed pockets in NTD. Three pockets have been found, to date, two of which have been shown to bind sialic acid (Awasthi et al, 2020;Fantini et al, 2020;Robson, 2020;Baker et al, 2021;Bò et al, 2021;Di Gaetano et al, 2021;Milanetti et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Insertions in the SARS-CoV-2 Spike N-Terminal Domain May Aid COVID-19 Transmission

Waman

Orengo

et al. 2021

Preprint

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Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is an ongoing pandemic that causes significant health/socioeconomic burden. Variants of concern (VOCs) have emerged which may affect transmissibility, disease severity and re-infection risk. Most studies focus on the receptor-binding domain (RBD) of the Spike protein. However, some studies suggest that the Spike N-terminal domain (NTD) may have a role in facilitating virus entry via sialic-acid receptor binding. Furthermore, most VOCs include novel NTD variants. Recent analyses demonstrated that NTD insertions in VOCs tend to lie close to loop regions likely to be involved in binding sialic acids. We extended the structural characterisation of these putative sugar binding pockets and explored whether variants could enhance the binding to sialic acids and therefore to the host membrane, thereby contributing to increased transmissibility. We found that recent NTD insertions in VOCs (i.e., Gamma, Delta and Omicron variants) and emerging variants of interest (VOIs) (i.e., Iota, Lambda, Theta variants) frequently lie close to known and putative sugar-binding pockets. For some variants, including the recent Omicron VOC, we find increases in predicted sialic acid binding energy, compared to the original SARS-CoV-2, which may contribute to increased transmission. We examined the similarity of NTD across a range of related Betacoronaviruses to determine whether the putative sugar-binding pockets are sufficiently similar to be exploited in drug design. Despite global sequence and structure similarity, most sialic-acid binding pockets of NTD vary across related coronaviruses. Typically, SARS-CoV-2 possesses additional loops in these pockets that increase contact with polysaccharides. Our work suggests ongoing evolutionary tuning of the sugar-binding pockets in the virus. Whilst three of the pockets are too structurally variable to be amenable to pan Betacoronavirus drug design, we detected a fourth pocket that is highly structurally conserved and could therefore be investigated in pursuit of a generic drug. Our structure-based analyses help rationalise the effects of VOCs and provide hypotheses for experiments. For example, the Omicron variant, which has increased binding to sialic acids in pocket 3, has a rather unique insertion near pocket 3. Our work suggests a strong need for experimental monitoring of VOC changes in NTD.

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“…Therefore, we selected the structures corresponding to the centroids of the clusters and studied such structures to search for possible binding regions with the Zernike polynomial formalism [ 22 , 23 , 24 , 25 ]. We found five equilibrium conformations (cluster centroids) for Fragment A (A1, A2, A3, A4, A5) and two for Fragment B (B1, B2).…”

Section: Results and Discussionmentioning

confidence: 99%

“…Recently, a new method based on the Zernike 2D polynomial expansion has been developed to evaluate whether and where two proteins can interact with each other to form a complex, based on their shape complementarity [ 22 , 23 ].…”

Section: Results and Discussionmentioning

confidence: 99%

“…To identify these binding regions, we use a method we have recently developed based on the mathematical formalism of the Zernike polynomial in two dimensions [ 22 , 23 ]. The method, characterized by a low computational cost compared to the commonly used version in three dimensions, examines portions of the molecular surface of two hypothetically interacting protein structures in terms of their local shape complementarity.…”

Section: Introductionmentioning

confidence: 99%

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A Computational Approach to Investigate TDP-43 RNA-Recognition Motif 2 C-Terminal Fragments Aggregation in Amyotrophic Lateral Sclerosis

et al. 2021

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Many of the molecular mechanisms underlying the pathological aggregation of proteins observed in neurodegenerative diseases are still not fully understood. Among the aggregate-associated diseases, Amyotrophic Lateral Sclerosis (ALS) is of relevant importance. In fact, although understanding the processes that cause the disease is still an open challenge, its relationship with protein aggregation is widely known. In particular, human TDP-43, an RNA/DNA binding protein, is a major component of the pathological cytoplasmic inclusions observed in ALS patients. Indeed, the deposition of the phosphorylated full-length TDP-43 in spinal cord cells has been widely studied. Moreover, it has also been shown that the brain cortex presents an accumulation of phosphorylated C-terminal fragments (CTFs). Even if it is debated whether the aggregation of CTFs represents a primary cause of ALS, it is a hallmark of TDP-43 related neurodegeneration in the brain. Here, we investigate the CTFs aggregation process, providing a computational model of interaction based on the evaluation of shape complementarity at the molecular interfaces. To this end, extensive Molecular Dynamics (MD) simulations were conducted for different types of protein fragments, with the aim of exploring the equilibrium conformations. Adopting a newly developed approach based on Zernike polynomials, able to find complementary regions in the molecular surface, we sampled a large set of solvent-exposed portions of CTFs structures as obtained from MD simulations. Our analysis proposes and assesses a set of possible association mechanisms between the CTFs, which could drive the aggregation process of the CTFs. To further evaluate the structural details of such associations, we perform molecular docking and additional MD simulations to propose possible complexes and assess their stability, focusing on complexes whose interacting regions are both characterized by a high shape complementarity and involve β3 and β5 strands at their interfaces.

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In-Silico Evidence for a Two Receptor Based Strategy of SARS-CoV-2

Cited by 65 publications

References 71 publications

Taste Dysfunction and Long COVID-19

Taste Dysfunction and Long COVID-19

Insertions in the SARS-CoV-2 Spike N-Terminal Domain May Aid COVID-19 Transmission

A Computational Approach to Investigate TDP-43 RNA-Recognition Motif 2 C-Terminal Fragments Aggregation in Amyotrophic Lateral Sclerosis

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