scholarly journals Naturally occurring SARS-CoV-2 gene deletions close to the spike S1/S2 cleavage site in the viral quasispecies of COVID19 patients

2020 ◽  
Vol 9 (1) ◽  
pp. 1900-1911 ◽  
Author(s):  
Cristina Andrés ◽  
Damir Garcia-Cehic ◽  
Josep Gregori ◽  
Maria Piñana ◽  
Francisco Rodriguez-Frias ◽  
...  
Keyword(s):  
Cleavage Site ◽  
Viral Quasispecies ◽  
Gene Deletions ◽  
Naturally Occurring

scholarly journals Naturally occurring SARS-CoV-2 gene deletions close to the spike S1/S2 cleavage site in the viral quasispecies of COVID19 patients

2020 ◽  
Author(s):  
Cristina Andres ◽  
Damir Garcia-Cehic ◽  
Josep Gregori ◽  
Maria Piñana ◽  
Francisco Rodriguez-Frias ◽  
...  
Keyword(s):  
Cleavage Site ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Stop Codon ◽  
Mutation Rates ◽  
Viral Quasispecies ◽  
Gene Deletions ◽  
Naturally Occurring ◽  
Viral Particles ◽  
Transmission Capability

ABSTRACTThe SARS-CoV-2 spike (S) protein, the viral mediator for binding and entry into the host cell, has sparked great interest as a target for vaccine development and treatments with neutralizing antibodies. Initial data suggest that the virus has low mutation rates, but its large genome could facilitate recombination, insertions, and deletions, as has been described in other coronaviruses. Here, we deep-sequenced the complete SARS-CoV-2 S gene from 18 patients (10 with mild and 8 with severe COVID-19), and found that the virus accumulates deletions upstream and very close to the S1/S2 cleavage site, generating a frameshift with appearance of a stop codon. These deletions were found in a small percentage of the viral quasispecies (2.2%) in samples from all the mild and only half the severe COVID-19 patients. Our results suggest that the virus may generate free S1 protein released to the circulation. We propose that natural selection has favored a “Don’t burn down the house” strategy, in which free S1 protein may compete with viral particles for the ACE2 receptor, thus reducing the severity of the infection and tissue damage without losing transmission capability.

A reactive center loop–based prediction platform to enhance the design of therapeutic SERPINs

2021 ◽  
Vol 118 (45) ◽  
pp. e2108458118
Author(s):  
Wariya Sanrattana ◽  
Thibaud Sefiane ◽  
Simone Smits ◽  
Nadine D. van Kleef ◽  
Marcel H. Fens ◽  
...  
Keyword(s):  
Cleavage Site ◽  
Serine Proteases ◽  
Protein C ◽  
Activated Protein C ◽  
Reactive Center Loop ◽  
Physiological Processes ◽  
Naturally Occurring ◽  
Reactive Center ◽  
Insight Into

Serine proteases are essential for many physiological processes and require tight regulation by serine protease inhibitors (SERPINs). A disturbed SERPIN–protease balance may result in disease. The reactive center loop (RCL) contains an enzymatic cleavage site between the P1 through P1’ residues that controls SERPIN specificity. This RCL can be modified to improve SERPIN function; however, a lack of insight into sequence–function relationships limits SERPIN development. This is complicated by more than 25 billion mutants needed to screen the entire P4 to P4’ region. Here, we developed a platform to predict the effects of RCL mutagenesis by using α1-antitrypsin as a model SERPIN. We generated variants for each of the residues in P4 to P4’ region, mutating them into each of the 20 naturally occurring amino acids. Subsequently, we profiled the reactivity of the resulting 160 variants against seven proteases involved in coagulation. These profiles formed the basis of an in silico prediction platform for SERPIN inhibitory behavior with combined P4 to P4’ RCL mutations, which were validated experimentally. This prediction platform accurately predicted SERPIN behavior against five out of the seven screened proteases, one of which was activated protein C (APC). Using these findings, a next-generation APC-inhibiting α1-antitrypsin variant was designed (KMPR/RIRA; / indicates the cleavage site). This variant attenuates blood loss in an in vivo hemophilia A model at a lower dosage than the previously developed variant AIKR/KIPP because of improved potency and specificity. We propose that this SERPIN-based RCL mutagenesis approach improves our understanding of SERPIN behavior and will facilitate the design of therapeutic SERPINs.

Detection of Activated Caspase-3 by a Cleavage Site-Directed Antiserum during Naturally Occurring DRG Neurons Apoptosis

1998 ◽  
Vol 247 (3) ◽  
pp. 780-784 ◽  
Author(s):  
Yoriko Kouroku ◽  
Koko Urase ◽  
Eriko Fujita ◽  
Kyoko Isahara ◽  
Yoshiyuki Ohsawa ◽  
...  
Keyword(s):  
Cleavage Site ◽  
Caspase 3 ◽  
Drg Neurons ◽  
Naturally Occurring

Growth properties and F protein cleavage site sequences of naturally occurring human parainfluenza type 2 viruses

Virology ◽  
1991 ◽  
Vol 184 (1) ◽  
pp. 87-92 ◽  
Author(s):  
Hisanori Bando ◽  
Mitsuo Kawano ◽  
Kunio Kondo ◽  
Masato Tsurudome ◽  
Hiroshi Komada ◽  
...  
Keyword(s):  
Cleavage Site ◽  
Protein Cleavage ◽  
F Protein ◽  
Naturally Occurring ◽  
Growth Properties

scholarly journals Unexpected Interfarm Transmission Dynamics during a Highly Pathogenic Avian Influenza Epidemic

2016 ◽  
Vol 90 (14) ◽  
pp. 6401-6411 ◽  
Author(s):  
Alice Fusaro ◽  
Luca Tassoni ◽  
Adelaide Milani ◽  
Joseph Hughes ◽  
Annalisa Salviato ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Avian Influenza ◽  
Cleavage Site ◽  
Highly Pathogenic Avian Influenza ◽  
Index Case ◽  
Genetic Data ◽  
Transmission Dynamics ◽  
Highly Pathogenic ◽  
Pathogenic Avian Influenza ◽  
Naturally Occurring

ABSTRACTNext-generation sequencing technology is now being increasingly applied to study the within- and between-host population dynamics of viruses. However, information on avian influenza virus evolution and transmission during a naturally occurring epidemic is still limited. Here, we use deep-sequencing data obtained from clinical samples collected from five industrial holdings and a backyard farm infected during the 2013 highly pathogenic avian influenza (HPAI) H7N7 epidemic in Italy to unravel (i) the epidemic virus population diversity, (ii) the evolution of virus pathogenicity, and (iii) the pathways of viral transmission between different holdings and sheds. We show a high level of genetic diversity of the HPAI H7N7 viruses within a single farm as a consequence of separate bottlenecks and founder effects. In particular, we identified the cocirculation in the index case of two viral strains showing a different insertion at the hemagglutinin cleavage site, as well as nine nucleotide differences at the consensus level and 92 minority variants. To assess interfarm transmission, we combined epidemiological and genetic data and identified the index case as the major source of the virus, suggesting the spread of different viral haplotypes from the index farm to the other industrial holdings, probably at different time points. Our results revealed interfarm transmission dynamics that the epidemiological data alone could not unravel and demonstrated that delay in the disease detection and stamping out was the major cause of the emergence and the spread of the HPAI strain.IMPORTANCEThe within- and between-host evolutionary dynamics of a highly pathogenic avian influenza (HPAI) strain during a naturally occurring epidemic is currently poorly understood. Here, we perform for the first time an in-depth sequence analysis of all the samples collected during a HPAI epidemic and demonstrate the importance to complement outbreak investigations with genetic data to reconstruct the transmission dynamics of the viruses and to evaluate the within- and between-farm genetic diversity of the viral population. We show that the evolutionary transition from the low pathogenic form to the highly pathogenic form occurred within the first infected flock, where we identified haplotypes with hemagglutinin cleavage site of different lengths. We also identify the index case as the major source of virus, indicating that prompt application of depopulation measures is essential to limit virus spread to other farms.

scholarly journals Amino Acid Preferences for a Critical Substrate Binding Subsite of Retroviral Proteases in Type 1 Cleavage Sites

2005 ◽  
Vol 79 (7) ◽  
pp. 4213-4218 ◽  
Author(s):  
Péter Bagossi ◽  
Tamás Sperka ◽  
Anita Fehér ◽  
János Kádas ◽  
Gábor Zahuczky ◽  
...  
Keyword(s):  
Amino Acid ◽  
Virus Type ◽  
Cleavage Site ◽  
Equine Infectious Anemia Virus ◽  
Leukemia Virus ◽  
Cell Leukemia Virus Type ◽  
Naturally Occurring ◽  
Retroviral Proteases ◽  
Hiv 1

ABSTRACT The specificities of the proteases of 11 retroviruses representing each of the seven genera of the family Retroviridae were studied using a series of oligopeptides with amino acid substitutions in the P2 position of a naturally occurring type 1 cleavage site (Val-Ser-Gln-Asn-Tyr↓Pro-Ile-Val-Gln; the arrow indicates the site of cleavage) in human immunodeficiency virus type 1 (HIV-1). This position was previously found to be one of the most critical in determining the substrate specificity differences of retroviral proteases. Specificities at this position were compared for HIV-1, HIV-2, equine infectious anemia virus, avian myeloblastosis virus, Mason-Pfizer monkey virus, mouse mammary tumor virus, Moloney murine leukemia virus, human T-cell leukemia virus type 1, bovine leukemia virus, human foamy virus, and walleye dermal sarcoma virus proteases. Three types of P2 preferences were observed: a subgroup of proteases preferred small hydrophobic side chains (Ala and Cys), and another subgroup preferred large hydrophobic residues (Ile and Leu), while the protease of HIV-1 preferred an Asn residue. The specificity distinctions among the proteases correlated well with the phylogenetic tree of retroviruses prepared solely based on the protease sequences. Molecular models for all of the proteases studied were built, and they were used to interpret the results. While size complementarities appear to be the main specificity-determining features of the S2 subsite of retroviral proteases, electrostatic contributions may play a role only in the case of HIV proteases. In most cases the P2 residues of naturally occurring type 1 cleavage site sequences of the studied proteases agreed well with the observed P2 preferences.

scholarly journals Naturally Occurring Amino Acid Polymorphisms in Human Immunodeficiency Virus Type 1 (HIV-1) Gag p7NC and the C-Cleavage Site Impact Gag-Pol Processing by HIV-1 Protease

Virology ◽  
2002 ◽  
Vol 292 (1) ◽  
pp. 137-149 ◽  
Author(s):  
Maureen M. Goodenow ◽  
Gregory Bloom ◽  
Stephanie L. Rose ◽  
Steven M. Pomeroy ◽  
Patricia O. O'Brien ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cleavage Site ◽  
Naturally Occurring ◽  
Immunodeficiency Virus ◽  
Hiv 1

The analysis of naturally occurring neuronal cell death by cleavage site-directed antiserum against Caspases

1998 ◽  
Vol 31 ◽  
pp. S329
Author(s):  
Yasuko Miho ◽  
Koko Urase ◽  
Yoriko Kouroku ◽  
Takeshi Mukasa ◽  
Yasuo Uchiyama ◽  
...  
Keyword(s):  
Cell Death ◽  
Cleavage Site ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Naturally Occurring

Genomic determinants of Furin cleavage in diverse European SARS-related bat coronaviruses

2021 ◽  
Author(s):  
Anna-Lena Sander ◽  
Andres Moreira-Soto ◽  
Stoian Yordanov ◽  
Ivan Toplak ◽  
Andrea Balboni ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Cleavage Site ◽  
Molecular Mechanisms ◽  
Rna Viruses ◽  
Viral Quasispecies ◽  
Furin Cleavage ◽  
Natural Origin ◽  
Furin Cleavage Site ◽  
Molecular Determinants ◽  
Horseshoe Bats

The furin cleavage site in SARS-CoV-2 is unique within the Severe acute respiratory syndrome-related coronavirus (SrC) species. We re-assessed diverse SrC from European horseshoe bats and reveal molecular determinants such as purine richness, RNA secondary structures and viral quasispecies potentially enabling furin cleavage. Furin cleavage thus likely emerged from the SrC bat reservoir via molecular mechanisms conserved across reservoir-bound RNA viruses, supporting a natural origin of SARS-CoV-2.

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