scholarly journals Neutral evolution test of the spike protein of SARS-CoV-2 and its implications in the binding to ACE2

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Georgina I. López-Cortés ◽  
Miryam Palacios-Pérez ◽  
Gabriel S. Zamudio ◽  
Hannya F. Veledíaz ◽  
Enrique Ortega ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Neutral Theory ◽  
Purifying Selection ◽  
Spike Protein ◽  
Health Concern ◽  
Neutral Evolution ◽  
Evolutionary Mechanisms ◽  
Theory Of Evolution ◽  
Selective Pressures

AbstractAs the SARS-CoV-2 has spread and the pandemic has dragged on, the virus continued to evolve rapidly resulting in the emergence of new highly transmissible variants that can be of public health concern. The evolutionary mechanisms that drove this rapid diversity are not well understood but neutral evolution should open the first insight. The neutral theory of evolution states that most mutations in the nucleic acid sequences are random and they can be fixed or disappear by purifying selection. Herein, we performed a neutrality test to better understand the selective pressures exerted over SARS-CoV-2 spike protein from homologue proteins of Betacoronavirus, as well as to the spikes from human clinical isolates of the virus. Specifically, Tyr and Asn have higher occurrence rates on the Receptor Binding Domain (RBD) and in the overall sequence of spike proteins of Betacoronavirus, whereas His and Arg have lower occurrence rates. The in vivo evolutionary phenomenon of SARS-CoV-2 shows that Glu, Lys, Phe, and Val have the highest probability of occurrence in the emergent viral particles. Amino acids that have higher occurrence than the expected by the neutral control, are favorable and are fixed in the sequence while the ones that have lower occurrence than expected, influence the stability and/or functionality of the protein. Our results show that most unique mutations either for SARS-CoV-2 or its variants of health concern are under selective pressures, which could be related either to the evasion of the immune system, increasing the virus’ fitness or altering protein – protein interactions with host proteins. We explored the consequences of those selected mutations in the structure and protein – protein interaction with the receptor. Altogether all these forces have shaped the spike protein and the continually evolving variants.

scholarly journals Neutral evolution test of the spike protein of SARS-CoV-2 and its implications in the binding to ACE2

2021 ◽  
Author(s):  
Georgina I. López-Cortés ◽  
Miryam Palacios-Pérez ◽  
Gabriel S. Zamudio ◽  
Hannya F. Veledíaz ◽  
Enrique Ortega ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Neutral Theory ◽  
Purifying Selection ◽  
Spike Protein ◽  
Health Concern ◽  
Neutral Evolution ◽  
Occurrence Rate ◽  
Evolutionary Mechanisms ◽  
Evolutionary Forces ◽  
Selective Pressures

Abstract As the SARS-CoV-2 has spread and the pandemic has dragged on, the virus continued to evolve rapidly resulting in the emergence of new highly transmissible variants that can be of public health concern. The evolutionary mechanisms that drove this rapid diversity are not well understood but neutral evolution should open the first insight. The neutral theory of evolution states that most mutations in the nucleic acid sequences are random and they can be fixed or disappear by purifying selection. Herein, we performed a neutrality test to better understand the selective pressures exerted over SARS-CoV-2 Spike protein, as well as in four of the identified health concern variants. Lys and Thr have higher occurrence rate on the Receptor Binding Domain (RBD) than in the overall sequence whereas Cys, His, and importantly Arg have low occurrence rate both in the whole protein and the RBD. Amino acids that have lower occurrence than the expected neutral control influence in the stability and or functionality of the protein. Our results show that most unique mutations either for SARS-CoV-2 or the variants of health concern are under selective pressures, which could be related either to the evasion of the immune system, increasing the virus’ fitness or altering protein – protein interactions with host proteins. Altogether all these forces have shaped the Spike protein. Understanding the evolutionary forces that act upon Spike protein may help designing better treatments and vaccines that target variants of health concern.

scholarly journals Implications of Two Opposing Variations of Neutral Theory

2018 ◽  
Vol 1 (1) ◽  
pp. 51-52
Author(s):  
Jonathan Bartlett
Keyword(s):  
Prior Information ◽  
Evolutionary Dynamics ◽  
Neutral Theory ◽  
Neutral Evolution ◽  
Theory Of Evolution ◽  
Comprehensive Theory ◽  
The Difference

This letter discusses the difference between neutral theory as an observation of present evolutionary dynamics compared to neutral theory as a more-or-less comprehensive theory of evolution.  The letter suggests that prior information, not neutral evolution itself, creates the patterns in the genome in ways that make the dynamics described by neutral theory possible in modern organisms.

scholarly journals In-vivo Protection from SARS-CoV-2 infection by ATN-161 in k18-hACE2 transgenic mice

2021 ◽  
Author(s):  
Amruta Narayanappa ◽  
Elizabeth B Engler-Chiurazzi ◽  
Isabel C Murray-Brown ◽  
Timothy E Gressett ◽  
Ifechukwude J Biose ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Viral Entry ◽  
Therapeutic Potential ◽  
Host Cells ◽  
Spike Protein ◽  
Cell Infection ◽  
Integrin Alpha5beta1 ◽  
Chemokine Ligand

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an infectious disease that has spread worldwide. Current treatments are limited in both availability and efficacy, such that improving our understanding of the factors that facilitate infection is urgently needed to more effectively treat infected individuals and to curb the pandemic. We and others have previously demonstrated the significance of interactions between the SARS-CoV-2 spike protein, integrin alpha5beta1 and human ACE2 to facilitate viral entry into host cells in vitro. We previously found that inhibition of integrin alpha5beta1 by the clinically validated small peptide ATN-161 inhibits these spike protein interactions and cell infection in vitro. In continuation with our previous findings, here we have further evaluated the therapeutic potential of ATN-161 on SARS-CoV-2 infection in k18-hACE2 transgenic (SARS-CoV-2 susceptible) mice in vivo. We discovered that treatment with single- or repeated intravenous doses of ATN-161 (1 mg/kg) within 48 hours after intranasal inoculation with SARS-CoV-2 lead to a reduction of lung viral load, viral immunofluorescence and improved lung histology in a majority of mice 72 hours post-infection. Furthermore, ATN-161 reduced SARS-CoV-2-induced increased expression of lung integrin alpha 5 and alpha v (an alpha 5-related integrin that has also been implicated in SARS-CoV-2 interactions) as well as the C-X-C motif chemokine ligand 10 (Cxcl10), further supporting the potential involvement of these integrins, and the anti-inflammatory potential of ATN-161, respectively, in SARS-CoV-2 infection. To the best of our knowledge, this is the first study demonstrating the potential therapeutic efficacy of targeting integrin alpha5beta1 in SARS-CoV-2 infection in vivo and supports the development of ATN-161 as a novel SARS-CoV-2 therapy.

The Generation of An Aptamer Inhibitor of Murine Von Willebrand Factor (VWF) Mediated Platelet Aggregation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4312-4312 ◽  
Author(s):  
Melissa Woelfel ◽  
Simon De Meyer ◽  
Patricia Wagner ◽  
Kathleen E McGinness ◽  
Denisa D. Wagner ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Protein Interactions ◽  
In Vitro Selection ◽  
Health Concern ◽  
Single Digit ◽  
Vein Wall ◽  
High Affinity

Abstract Abstract 4312 Venous thromboembolism (VTE) is a national health concern, with an occurrence of over 900,000 cases per year and over 300,000 deaths per year. The total number of cases of VTE and the incidence of VTE-related deaths exceeds those related to both myocardial infarction and stroke. With an aging population, the incidence of VTE has also been increasing. Current treatment of venous thromboembolism with anti-coagulation is not optimal. There is a risk of bleeding, thrombus extension, pain and swelling as well as a recurrence rate of 3–9%. A significant inflammatory response occurs with venous thromboembolism. This inflammation can influence the extent of thrombosis, vein wall fibrosis and valve damage in the thrombosed vein. In a high percentage of VTE patients a condition of venous insufficiency known as post-thrombotic syndrome (PTS) can develop. PTS is associated with stasis ulceration, dermatitis and edema. Venous thrombogenesis is influenced by platelet (PLT) and leukocyte (WBC) adhesion as well as interactions between these cells. There is growing evidence to suggest that VWF interactions with PLT GPIbα can mediate some of these early events. This is evidenced by the reduction in PLT/WBC recruitment and reduced thrombus growth seen in either VWF or GPIbα deficient mice. These data point to a role for VWF in VTE. We sought to develop an aptamer to mouse VWF that would inhibit its interactions with platelet GPIbα. The availability of this tool would support investigations into the role of VWF in mouse models of VTE. Aptamers are oligonucleotides that fold into three-dimensional structures and specifically bind to ligands with high affinity. Aptamers bound to proteins can modify and/or inhibit protein-protein interactions. Using an in vitro selection method known as Systematic Evolution of Ligands by EXponential enrichment (SELEX), we generated aptamers that bind to murine VWF (mVWF) from a modified RNA pool. Nine of these aptamers bind to mVWF with single-digit or sub- nanomolar affinity. A subset of these aptamers also binds to human VWF (hVWF). The aptamers that bind to hVWF inhibit platelet adhesion/aggregation in human whole blood. Further in vitro characterization has demonstrated that five of these aptamers specifically inhibit the interaction between mVWF and recombinant human GPIbα, but do not interfere with the binding of mVWF to collagen. These five aptamers were also active in vivo in a FeCl3-induced thrombosis model in mice. Intravenous injection of the anti-mVWF aptamers prolonged time to occlusion from a baseline of 10–15 minutes to either 25–35 minutes or >40 minutes in this model, depending on the aptamer. These results demonstrate that we have identified high affinity aptamers to mVWF that specifically disrupt mVWF binding to platelets and have an antithrombotic effect in an in vivo mouse model of thrombosis. These aptamers will allow us to investigate the role of VWF in murine models of venous thrombosis. This project was supported by Award Number R01HL095091 from the National Heart, Lung, And Blood Institute. Disclosures: Woelfel: Archemix Corporation: Employment. Wagner:Archemix Corporation: Employment. McGinness:Archemix Corporation: Employment. Schaub:Archemix Corporation: Employment.

scholarly journals Target related in silico analysis of Bergenin and tuberculosis management

Biomedicine ◽  
2021 ◽  
Vol 40 (4) ◽  
pp. 474-481
Author(s):  
Virupaksha A. Bastikar ◽  
Alpana Bastikar ◽  
Pramodkumar P. Gupta ◽  
Sandeep R. Pai ◽  
Santosh S. Chhajed
Keyword(s):  
Protein Interactions ◽  
In Silico ◽  
Biological Process ◽  
In Silico Analysis ◽  
Enrichment Analysis ◽  
Binding Mode ◽  
Health Concern ◽  
Silico Analysis

Introduction and Aim: Tuberculosis (TB) is a global health concern, claiming two million lives every year. Although an oldest known human infectious disease, researcher is falling short of giving out an effective and reliable vaccine or therapy. The current antimycobacterial drugs include Isoniazid, Ethambutol, Rifampicin and Pyrazinemamide available in market, but most of these are known to have certain adverse effects. Hence there is an increase in demand for natural products with anti-tuberculosis activity with no or limited side effects. Indian traditional systems of medicine have a plethora of promising plants for treatment of tuberculosis, of which Bergenin is the most well established and extensively used compound. The main aim of this research was to investigate the role of Bergenin as an anti-tuberculosis agent with the help of in-silico analysis and protein interaction studies. Materials and Methods: In the present study 04 known 3-dimensional crystallized anti-tubercular drug target is considered and retrieved from PDB. Drug Isoniazid, Ethambutol, Rifampicin, Pyrazineamide and phytochemical Bergenin were retrieved, sketched and geometrically optimized. Molecular docking is carried to understand the binding mode and its core interactions. ADMET properties were calculated in assessment of the toxicity. Protein-protein interactions and enrichment analysis is carried out to understand the biological process involved with rpsA protein. Results: In the present study other than Rifampicin, Bergenin reported with better binding energy and similar pharmacophoric interaction pattern as compared to all the 04 indigenous inhibitors. The PPI network and enrichment analysis predicts the plausible biological process involved with rpsA protein and can be further targeted in treatment of tuberculosis. Conclusion: The results showed that Bergenin was better than and competent with the existing drugs and can be used as an anti-tuberculosis agent if studied in-vitro and in-vivo for its activity.

Phospholipid-Protein Interactions in the Formation of Prothrombin Activator

1965 ◽  
Vol 14 (03/04) ◽  
pp. 431-444 ◽  
Author(s):  
E. R Cole ◽  
J. L Koppel ◽  
J. H Olwin
Keyword(s):  
Complex Formation ◽  
Protein Interactions ◽  
Calcium Ions ◽  
Fixed Number ◽  
Factor V ◽  
Clotting Factors ◽  
Number Of Binding Sites ◽  
C Complex ◽  
Autoprothrombin C

SummarySince Ac-globulin (factor V) is involved in the formation of prothrombin activator, its ability to complex with phospholipids was studied. Purified bovine Ac-globulin was complexed to asolectin, there being presumably a fixed number of binding sites on the phospholipid micelle for Ac-globulin. In contrast to the requirement for calcium ions in the formation of complexes between asolectin and autoprothrombin C, calcium ions were not required for complex formation between asolectin and Ac-globulin to occur ; in fact, the presence of calcium prevented complex formation occurring, the degree of inhibition being dependent on the calcium concentration. By treating isolated, pre-formed aso- lectin-Ac-globulin complexes with calcium chloride solutions, Ac-globulin could be recovered in a much higher state of purity and essentially free of asolectin.Complete activators were formed by first preparing the asolectin-calcium- autoprothrombin C complex and then reacting the complex with Ac-globulin. A small amount of this product was very effective as an activator of purified prothrombin without further addition of calcium or any other cofactor. If the autoprothrombin C preparation used to prepare the complex was free of traces of prothrombin, the complete activator was stable for several hours at room temperature. Stable preparations of the complete activator were centrifuged, resulting in the sedimentation of most of the activity. Experimental evidence also indicated that activator activity was highest when autoprothrombin C and Ac-globulin were complexed to the same phospholipid micelle, rather than when the two clotting factors were complexed to separate micelles. These data suggested that the in vivo prothrombin activator may be a sedimentable complex composed of a thromboplastic enzyme, calcium, Ac-globulin and phospholipid.

Probing the 14-3-3 Isoform-Specificity Profile of Interactions Stabilized by Fusicoccin A

2020 ◽  
Author(s):  
James Frederich ◽  
Ananya Sengupta ◽  
Josue Liriano ◽  
Ewa A. Bienkiewicz ◽  
Brian G. Miller
Keyword(s):  
Protein Interactions ◽  
Neurological Diseases ◽  
Adapter Proteins ◽  
Protein Protein Interactions ◽  
Specific Expression ◽  
Individual Client ◽  
Isoform Specificity ◽  
Fusicoccin A

Fusicoccin A (FC) is a fungal phytotoxin that stabilizes protein–protein interactions (PPIs) between 14-3-3 adapter proteins and their phosphoprotein interaction partners. In recent years, FC has emerged as an important chemical probe of human 14-3-3 PPIs implicated in cancer and neurological diseases. These previous studies have established the structural requirements for FC-induced stabilization of 14-3-3·client phosphoprotein complexes; however, the effect of different 14-3-3 isoforms on FC activity has not been systematically explored. This is a relevant question for the continued development of FC variants because there are seven distinct isoforms of 14-3-3 in humans. Despite their remarkable sequence and structural similarities, a growing body of experimental evidence supports both tissue-specific expression of 14-3-3 isoforms and isoform-specific functions <i>in vivo</i>. Herein, we report the isoform-specificity profile of FC <i>in vitro</i>using recombinant human 14-3-3 isoforms and a focused library of fluorescein-labeled hexaphosphopeptides mimicking the C-terminal 14-3-3 recognition domains of client phosphoproteins targeted by FC in cell culture. Our results reveal modest isoform preferences for individual client phospholigands and demonstrate that FC differentially stabilizes PPIs involving 14-3-3s. Together, these data provide strong motivation for the development of non-natural FC variants with enhanced selectivity for individual 14-3-3 isoforms.

Chickpea (Cicer arietinum L.) Lectin Exhibit Inhibition of ACE-I, α-amylase and α-glucosidase Activity

2019 ◽  
Vol 26 (7) ◽  
pp. 494-501 ◽  
Author(s):  
Sameer Suresh Bhagyawant ◽  
Dakshita Tanaji Narvekar ◽  
Neha Gupta ◽  
Amita Bhadkaria ◽  
Ajay Kumar Gautam ◽  
...  
Keyword(s):  
Biological Effects ◽  
Exchange Chromatography ◽  
Health Concern ◽  
Carbohydrate Binding ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Ic50 Values ◽  
Chickpea Lectin

Background: Diabetes and hypertension are the major health concern and alleged to be of epidemic proportions. This has made it a numero uno subject at various levels of investigation. Glucosidase inhibitor provides the reasonable option in treatment of Diabetes Mellitus (DM) as it specifically targets post prandial hyperglycemia. The Angiotensin Converting Enzyme (ACE) plays an important role in hypertension. Therefore, inhibition of ACE in treatment of elevated blood pressure attracts special interest of the scientific community. Chickpea is a food legume and seeds contain carbohydrate binding protein- a lectin. Some of the biological properties of this lectin hitherto been elucidated. Methods: Purified by ion exchange chromatography, chickpea lectin was tested for its in vitro antioxidant, ACE-I inhibitory and anti-diabetic characteristic. Results: Lectin shows a characteristic improvement over the synthetic drugs like acarbose (oral anti-diabetic drug) and captopril (standard antihypertensive drug) when, their IC50 values are compared. Lectin significantly inhibited α-glucosidase and α-amylase in a concentration dependent manner with IC50 values of 85.41 ± 1.21 ҝg/ml and 65.05 ± 1.2 µg/ml compared to acarbose having IC50 70.20 ± 0.47 value of µg/ml and 50.52 ± 1.01 µg/ml respectively. β-Carotene bleaching assay showed antioxidant activity of lectin (72.3%) to be as active as Butylated Hydroxylanisole (BHA). In addition, lectin demonstrated inhibition against ACE-I with IC50 value of 57.43 ± 1.20 µg/ml compared to captopril. Conclusion: Lectin demonstrated its antioxidant character, ACE-I inhibition and significantly inhibitory for α-glucosidase and α-amylase seems to qualify as an anti-hyperglycemic therapeutic molecule. The biological effects of chickpea lectin display potential for reducing the parameters of medically debilitating conditions. These characteristics however needs to be established under in vivo systems too viz. animals through to humans.

Approach in improving potency and selectivity of kinase inhibitors: Allosteric kinase inhibitors

2020 ◽  
Vol 21 ◽  
Author(s):  
Shangfei Wei ◽  
Tianming Zhao ◽  
Jie Wang ◽  
Xin Zhai
Keyword(s):  
Protein Interactions ◽  
Kinase Inhibitors ◽  
Binding Modes ◽  
Allosteric Inhibitors ◽  
Wide Range ◽  
Allosteric Sites ◽  
Protein Functions ◽  
Regulate Protein

: Allostery is an efficient and particular regulatory mechanism to regulate protein functions. Different from conserved orthosteric sites, allosteric sites have distinctive functional mechanism to form the complex regulatory network. In drug discovery, kinase inhibitors targeting the allosteric pockets have received extensive attention for the advantages of high selectivity and low toxicity. The approval of trametinib as the first allosteric inhibitor validated that allosteric inhibitors could be used as effective therapeutic drugs for treatment of diseases. To date, a wide range of allosteric inhibitors have been identified. In this perspective, we outline different binding modes and potential advantages of allosteric inhibitors. In the meantime, the research processes of typical and novel allosteric inhibitors are described briefly in terms of structureactivity relationships, ligand-protein interactions and in vitro and in vivo activity. Additionally, challenges as well as opportunities are presented.

Molecular basis of adaptive evolution of sperm motility involved in in vivo fertilization of terrestrial animals

Impact ◽  
2020 ◽  
Vol 2020 (6) ◽  
pp. 73-75
Author(s):  
Akihiko Watanabe
Keyword(s):  
Sexual Reproduction ◽  
Sperm Motility ◽  
Asexual Reproduction ◽  
Acrosome Reaction ◽  
Sperm Morphology ◽  
Adaptive Potential ◽  
Selective Pressures ◽  
The Face ◽  
Genetic Profiles

One of the unifying traits of life on this planet is reproduction, or life's ability to make copies of itself. The mode of reproduction has evolved over time, having almost certainly begun with simple asexual reproduction when the ancestral single celled organism divided into two. Since these beginnings' life has tried out numerous strategies, and perhaps one of the most important and successful has been sexual reproduction. This form of reproduction relies on the union of gametes, otherwise known as sperm and egg. Evolutionarily, sexual reproduction allows for greater adaptive potential because the genes of two unique individuals have a chance to recombine and mix in order to produce a new individual. Unlike asexual reproduction which produces genetically-identical clones of the parent individual, sex produces offspring with novel genes and combinations of genes. Therefore, in the face of new selective pressures there is a higher chance that one of these novel genetic profiles will produce an adaptation that is advantageous in the new circumstances. Dr Akihiko Watanabe is a reproductive biologist based in the Department of Biology, Faculty of Science Yamagata University in Japan, he is currently working on three research projects; a comparative study on the signalling pathways for inducing sperm motility and acrosome reaction in amphibians, the mechanism behind the adaptive modification of sperm morphology and motility, and the origin of sperm motility initiating substance (SMIS).

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