scholarly journals Identifying Primate ACE2 Variants That Confer Resistance to SARS-CoV-2

2021 ◽  
Author(s):  
Maloyjo Joyraj Bhattacharjee ◽  
Jinn-Jy Lin ◽  
Chih-Yao Chang ◽  
Yu-Ting Chiou ◽  
Tian-Neng Li ◽  
...  
Keyword(s):  
Binding Affinity ◽  
New World Monkeys ◽  
Strong Reduction ◽  
Protein Structure Analysis ◽  
S Protein ◽  
Human Sequence ◽  
Angiotensin I Converting Enzyme ◽  
The Common ◽  
Ace2 Gene ◽  
Prosimian Species

Abstract SARS-CoV-2 infects humans through the binding of viral S-protein (spike protein) to human angiotensin I converting enzyme 2 (ACE2). The structure of the ACE2-S-protein complex has been deciphered and we focused on the 27 ACE2 residues that bind to S-protein. From human sequence databases, we identified nine ACE2 variants at ACE2–S-protein binding sites. We used both experimental assays and protein structure analysis to evaluate the effect of each variant on the binding affinity of ACE2 to S-protein. We found one variant causing complete binding disruption, two and three variants, respectively, strongly and mildly reducing the binding affinity, and two variants strongly enhancing the binding affinity. We then collected the ACE2 gene sequences from 57 nonhuman primates. Among the 6 apes and 20 Old World monkeys (OWMs) studied, we found no new variants. In contrast, all 11 New World monkeys (NWMs) studied share four variants each causing a strong reduction in binding affinity, the Philippine tarsier also possesses three such variants, and 18 of the 19 prosimian species studied share one variant causing a strong reduction in binding affinity. Moreover, one OWM and three prosimian variants increased binding affinity by >50%. Based on these findings, we proposed that the common ancestor of primates was strongly resistant to and that of NWMs was completely resistant to SARS-CoV-2 and so is the Philippine tarsier, whereas apes and OWMs, like most humans, are susceptible. This study increases our understanding of the differences in susceptibility to SARS-CoV-2 infection among primates.

scholarly journals Angiotensin I–Converting Enzyme Type 2 (ACE2) Gene Therapy Improves Glycemic Control in Diabetic Mice

Diabetes ◽  
2010 ◽  
Vol 59 (10) ◽  
pp. 2540-2548 ◽  
Author(s):  
Sharell M. Bindom ◽  
Chetan P. Hans ◽  
Huijing Xia ◽  
A. Hamid Boulares ◽  
Eric Lazartigues
Keyword(s):  
Gene Therapy ◽  
Glycemic Control ◽  
Converting Enzyme ◽  
Diabetic Mice ◽  
Angiotensin I ◽  
Angiotensin I Converting Enzyme ◽  
Ace2 Gene

scholarly journals Comprehensive Structural and Molecular Comparison of Spike Proteins of SARS-CoV-2, SARS-CoV and MERS-CoV, and Their Interactions with ACE2

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2638 ◽  
Author(s):  
Ma’mon M. Hatmal ◽  
Walhan Alshaer ◽  
Mohammad A. I. Al-Hatamleh ◽  
Malik Hatmal ◽  
Othman Smadi ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Binding Motif ◽  
Intermediate Hosts ◽  
Protein Structure Analysis ◽  
S Protein ◽  
Binding Characteristics ◽  
Protein Receptor ◽  
Genes Encoding ◽  
Tertiary Protein Structure ◽  
Molecular Comparison

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has recently emerged in China and caused a disease called coronavirus disease 2019 (COVID-19). The virus quickly spread around the world, causing a sustained global outbreak. Although SARS-CoV-2, and other coronaviruses, SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV) are highly similar genetically and at the protein production level, there are significant differences between them. Research has shown that the structural spike (S) protein plays an important role in the evolution and transmission of SARS-CoV-2. So far, studies have shown that various genes encoding primarily for elements of S protein undergo frequent mutation. We have performed an in-depth review of the literature covering the structural and mutational aspects of S protein in the context of SARS-CoV-2, and compared them with those of SARS-CoV and MERS-CoV. Our analytical approach consisted in an initial genome and transcriptome analysis, followed by primary, secondary and tertiary protein structure analysis. Additionally, we investigated the potential effects of these differences on the S protein binding and interactions to angiotensin-converting enzyme 2 (ACE2), and we established, after extensive analysis of previous research articles, that SARS-CoV-2 and SARS-CoV use different ends/regions in S protein receptor-binding motif (RBM) and different types of interactions for their chief binding with ACE2. These differences may have significant implications on pathogenesis, entry and ability to infect intermediate hosts for these coronaviruses. This review comprehensively addresses in detail the variations in S protein, its receptor-binding characteristics and detailed structural interactions, the process of cleavage involved in priming, as well as other differences between coronaviruses.

scholarly journals Differences in neutralizing antigenicity between laboratory and clinical isolates of HCoV-229E isolated in Japan in 2004–2008 depend on the S1 region sequence of the spike protein

2012 ◽  
Vol 93 (9) ◽  
pp. 1908-1917 ◽  
Author(s):  
Kazuya Shirato ◽  
Miyuki Kawase ◽  
Oshi Watanabe ◽  
Chika Hirokawa ◽  
Shutoku Matsuyama ◽  
...  
Keyword(s):  
Protein A ◽  
Laboratory Strain ◽  
Clinical Isolates ◽  
Pseudotyped Virus ◽  
S Protein ◽  
Human Sera ◽  
Antigenic Phenotype ◽  
Vesicular Stomatitis ◽  
The Common ◽  
The Difference

Human coronavirus (HCoV) is a causative agent of the common cold. Although HCoV is highly prevalent in the world, studies of the genomic and antigenic details of circulating HCoV strains have been limited. In this study, we compared four Japanese isolates with the standard HCoV-229E strain obtained from ATCC (ATCC-VR740) by focusing on the spike (S) protein, a major determinant of neutralizing antigen and pathogenicity. The isolates were found to have nucleotide deletions and a number of sequence differences in the S1 region of the S protein. We compared two of the Japanese isolates with the ATCC-VR740 strain by using virus-neutralizing assays consisting of infectious HCoV-229E particles and vesicular stomatitis virus (VSV)-pseudotyped virus carrying the HCoV-229E S protein. The two clinical isolates (Sendai-H/1121/04 and Niigata/01/08) did not react with antiserum to the ATCC-VR740 strain via the neutralizing test. We then constructed a pseudotype VSV-harboured chimeric S protein with the ATCC S1 and Sendai S2 regions or that with Sendai S1 and ATCC S2 regions and compared them by a neutralization test. The results revealed that the difference in the neutralizing antigenicity depends on the S1 region. This different antigenic phenotype was also confirmed by a neutralizing test with clinically isolated human sera. These results suggest that the HCoV-229E viruses prevalent in Japan are quite different from the laboratory strain ATCC-VR740 in terms of the S sequence and neutralization antigenicity, which is attributed to the difference in the S1 region.

Anatomical description and morphometry of the skeleton of the common marmoset (Callithrix jacchus)

2012 ◽  
Vol 46 (2) ◽  
pp. 152-163 ◽  
Author(s):  
C Casteleyn ◽  
J Bakker ◽  
S Breugelmans ◽  
I Kondova ◽  
J Saunders ◽  
...  
Keyword(s):  
Biomedical Research ◽  
Third Molar ◽  
Common Marmoset ◽  
Callithrix Jacchus ◽  
New World Monkeys ◽  
Thoracic Vertebrae ◽  
Xiphoid Process ◽  
Caudal Vertebrae ◽  
Thoracolumbar Region ◽  
The Common

Callithrix jacchus (common marmoset) is regularly used in biomedical research, including for studies involving the skeleton. To support these studies, skeletons of healthy animals that had been euthanized for reasons not interfering with skeletal anatomy were prepared. The marmoset dental formula 2I-1C-3P-2M of each oral quadrant is atypical for New World monkeys which commonly possess a third molar. Seven cervical, 12–13 thoracic, 7–6 lumbar, 2–3 sacral and 26–29 caudal vertebrae are present, the thoracolumbar region always comprising 19 vertebrae. A sigmoid clavicle connects the scapula with the manubrium of the sternum. Depending on the number of thoracic vertebrae, 4–5 sternebrae are located between the manubrium and xiphoid process. Wide interosseous spaces separate the radius from the ulna, and the tibia from the fibula. A small sesamoid bone is inserted in the m. abductor digiti primi longus at the medial border of the carpus, a pair of ovoid sesamoid bones is located at the palmar/plantar sides of the trochleae of each metapodial bone, and round fabellae articulate with the proximal surfaces of the femoral condyles. Male marmosets possess a small penile bone. Both the front and hind feet have five digits. The hallux possesses a flat nail, whereas all other digits present curved claws. Interestingly, a central bone is present in both the carpus and tarsus. This study provides a description and detailed illustrations of the skeleton of the common marmoset as an anatomical guide for further biomedical research.

scholarly journals Computational saturation mutagenesis of SARS-CoV-1 spike glycoprotein: stability, binding affinity, and comparison with SARS-CoV-2

2021 ◽  
Author(s):  
Adebiyi Sobitan ◽  
Vidhyanand Mahase ◽  
Raina Rhoades ◽  
Dejaun Williams ◽  
Dongxiao Liu ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Structure Alignment ◽  
Saturation Mutagenesis ◽  
Missense Mutations ◽  
Spike Glycoprotein ◽  
S Protein ◽  
Glycosylation Sites ◽  
Protein Amino Acids ◽  
Host Cell Surface ◽  
The Stability

Severe Acute respiratory syndrome coronavirus (SARS-CoV-1) attaches to the host cell surface to initiate the interaction between the receptor-binding domain (RBD) of its spike glycoprotein (S) and the human Angiotensin-converting enzyme (hACE2) receptor. SARS-CoV-1 mutates frequently because of its RNA genome, which challenges the antiviral development. Here, we performed computational saturation mutagenesis of the S protein of SARS-CoV-1 to identify the residues crucial for its functions. We used the structure-based energy calculations to analyze the effects of the missense mutations on the SARS-CoV-1 S stability and the binding affinity with hACE2. The sequence and structure alignment showed similarities between the S proteins of SARS-CoV-1 and SARS-CoV-2. Interestingly, we found that target mutations of S protein amino acids generate similar effects on their stabilities between SARS-CoV-1 and SARS-CoV-2. For example, G839W of SARS-CoV-1 corresponds to G857W of SARS-CoV-2, which decrease the stability of their S glycoproteins. The viral mutation analysis of the two different SARS-CoV-1 isolates showed that mutations, T487S and L472P, weakened the S-hACE2 binding of the 2003-2004 SARS-CoV-1 isolate. In addition, the mutations of L472P and F360S destabilized the 2003-2004 viral isolate. We further predicted that many mutations on N-linked glycosylation sites would increase the stability of the S glycoprotein. Our results can be of therapeutic importance in the design of antivirals or vaccines against SARS-CoV-1 and SARS-CoV-2.

scholarly journals Harnessing the Sars-cov-2 Spike Protein Binding Affinity to Ace2 Receptor Through Narcotinic Compounds Combined With Adjuvants: an in Silico Insight

2021 ◽  
Author(s):  
Saeedeh Mohammadi ◽  
Esmail Doustkhah ◽  
Nader Sakhaee ◽  
Ayoub Esmailpour ◽  
Mohammad Esmailpour
Keyword(s):  
Binding Affinity ◽  
In Silico ◽  
Muramyl Dipeptide ◽  
Docking Studies ◽  
Spike Protein ◽  
Binding Affinities ◽  
Narcotic Analgesics ◽  
S Protein ◽  
Suitable Combination ◽  
Spike Proteins

Abstract Protein products of SARS-CoV-2 spike (S) coding gene sequence, were all analyzed and compared to other SARS-CoV S proteins to elucidate structural similarities of spike proteins. A homology modeling of SARS-CoV-2 S protein was obtained and used in molecular docking studies to find binding affinities of spike protein for angiotensin-converting enzyme 2 (ACE2). The two most important binding sites of S protein, namely, RBD and CTD, critically responsible for binding interactions, were identified. Finally, binding affinity of RBD and CTD domains of S protein with narcotic analgesics are studied. Moreover, interactions of ACE2 receptor- S protein with narcotic compounds when mixed with small molecule adjuvants to improve the immune response and increase the efficacy of potential vaccines, were taken into consideration. In-silico results suggest that the combination of narcotine hemiacetal with mannide monooleate shows a stronger binding affinity with CTD, while carprofen-muramyl dipeptide and squalene have stronger binding affinities for the RBD portion of S protein. Thus, a suitable combination of these narcotic is proposed to yield potent site-blocking efficacy for ACE2 receptor against SARS-CoV-2 spike proteins.

scholarly journals Fast assessment of human receptor-binding capability of 2019 novel coronavirus (2019-nCoV)

2020 ◽  
Author(s):  
Qiang Huang ◽  
Andreas Herrmann
Keyword(s):  
Binding Affinity ◽  
Receptor Binding ◽  
Large Scale ◽  
Quantitative Methods ◽  
Complex Structure ◽  
Protein Docking ◽  
Monte Carlo Algorithm ◽  
S Protein ◽  
Transmission Capability ◽  
Human Receptor

AbstractThe outbreaks of 2002/2003 SARS, 2012/2015 MERS and 2019/2020 Wuhan respiratory syndrome clearly indicate that genome evolution of an animal coronavirus (CoV) may enable it to acquire human transmission ability, and thereby to cause serious threats to global public health. It is widely accepted that CoV human transmission is driven by the interactions of its spike protein (S-protein) with human receptor on host cell surface; so, quantitative evaluation of these interactions may be used to assess the human transmission capability of CoVs. However, quantitative methods directly using viral genome data are still lacking. Here, we perform large-scale protein-protein docking to quantify the interactions of 2019-nCoV S-protein receptor-binding domain (S-RBD) with human receptor ACE2, based on experimental SARS-CoV S-RBD-ACE2 complex structure. By sampling a large number of thermodynamically probable binding conformations with Monte Carlo algorithm, this approach successfully identified the experimental complex structure as the lowest-energy receptor-binding conformations, and hence established an experiment-based strength reference for evaluating the receptor-binding affinity of 2019-nCoV via comparison with SARS-CoV. Our results show that this binding affinity is about 73% of that of SARS-CoV, supporting that 2019-nCoV may cause human transmission similar to that of SARS-CoV. Thus, this study presents a method for rapidly assessing the human transmission capability of a newly emerged CoV and its mutant strains, and demonstrates that post-genome analysis of protein-protein interactions may provide early scientific guidance for viral prevention and control.

scholarly journals Camel Hemorphins Exhibit a More Potent Angiotensin-I Converting Enzyme Inhibitory Activity than Other Mammalian Hemorphins: An In Silico and In Vitro Study

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 486 ◽  
Author(s):  
Amanat Ali ◽  
Seham Abdullah Rashed Alzeyoudi ◽  
Shamma Abdulla Almutawa ◽  
Alya Nasir Alnajjar ◽  
Yusra Al Dhaheri ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Active Site ◽  
Inhibitory Activity ◽  
In Vitro Study ◽  
Ace Inhibition ◽  
Converting Enzyme ◽  
Angiotensin I ◽  
Angiotensin I Converting Enzyme ◽  
Dynamics Simulations

Angiotensin-I converting enzyme (ACE) is a zinc metallopeptidase that has an important role in regulating the renin-angiotensin-aldosterone system (RAAS). It is also an important drug target for the management of cardiovascular diseases. Hemorphins are endogenous peptides that are produced by proteolytic cleavage of beta hemoglobin. A number of studies have reported various therapeutic activities of hemorphins. Previous reports have shown antihypertensive action of hemorphins via the inhibition of ACE. The sequence of hemorphins is highly conserved among mammals, except in camels, which harbors a unique Q>R variation in the peptide. Here, we studied the ACE inhibitory activity of camel hemorphins (LVVYPWTRRF and YPWTRRF) and non-camel hemorphins (LVVYPWTQRF and YPWTQRF). Computational methods were used to determine the most likely binding pose and binding affinity of both camel and non-camel hemorphins within the active site of ACE. Molecular dynamics simulations showed that the peptides interacted with critical residues in the active site of ACE. Notably, camel hemorphins showed higher binding affinity and sustained interactions with all three subsites of the ACE active site. An in vitro ACE inhibition assay showed that the IC50 of camel hemorphins were significantly lower than the IC50 of non-camel hemorphins.

Association study of ACE2 (angiotensin I-converting enzyme 2) gene polymorphisms with coronary heart disease and myocardial infarction in a Chinese Han population

2006 ◽  
Vol 111 (5) ◽  
pp. 333-340 ◽  
Author(s):  
Wei Yang ◽  
Wentao Huang ◽  
Shaoyong Su ◽  
Biao Li ◽  
Weiyan Zhao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Odds Ratio ◽  
Converting Enzyme ◽  
Angiotensin I ◽  
Angiotensin I Converting Enzyme ◽  
Common Genetic Variants ◽  
Male Subjects ◽  
Ace2 Gene

Results are accumulating that ACE2 (angiotensin I-converting enzyme 2) might act as a protective protein for cardiovascular diseases; however, only a few studies in human populations have been carried out. This prompted us to perform a case-control study to investigate the relationship of ACE2 polymorphisms with CHD (coronary heart disease) and MI (myocardial infarction). Three single nucleotide polymorphisms in the ACE2 gene (1075A/G, 8790A/G and 16854G/C) were genotyped by PCR-RFLP (restriction-fragment-length polymorphism) in 811 patients with CHD (of which 508 were patients with MI) and 905 normal controls in a Chinese population. The polymorphisms were in linkage disequilibrium (r2=0.854–0.973). Analyses were conducted by gender, because the ACE2 gene is on the X chromosome. In females, an association was detected with MI for 1075A/G (P=0.026; odds ratio=1.98) and 16854G/C (P=0.028; odds ratio=1.97) in recessive models after adjusting for covariates. In male subjects, two haplotypes (AAG and GGC) were common in frequency. In male subjects not consuming alcohol, the haplotype GGC was associated with a 1.76-fold risk of CHD [95% CI (confidence interval), 1.15–2.69; P=0.007] and a 1.77-fold risk of MI (95% CI, 1.12–2.81; P=0.015) with environmental factors adjusted, when compared with the most common haplotype AAG. In conclusion, the results of the present study indicate that common genetic variants in the ACE2 gene might impact on MI in females, and may possibly interact with alcohol consumption to affect the risk of CHD and MI in Chinese males.

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