scholarly journals Novel Mutations in NSP1 and PLPro of SARS-CoV-2 NIB-1 Genome Mount for Effective Therapeutics

2020 ◽  
Author(s):  
Mohammad Uzzal Hossain ◽  
Arittra Bhattacharjee ◽  
Md. Tabassum Hossain Emon ◽  
Zeshan Mahmud Chowdhury ◽  
Md. Golam Mosaib ◽  
...  
Keyword(s):  
Etiologic Agent ◽  
Structural Protein ◽  
Wild Type ◽  
Viral Isolate ◽  
Novel Mutations ◽  
Therapeutic Development ◽  
Sanger Method ◽  
Conserved Residue ◽  
New Mutations

AbstractSevere Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the etiologic agent of Coronavirus Disease-2019 (COVID-19), is rapidly accumulating new mutations. Analysis of these mutations is necessary for gaining knowledge regarding different aspects of therapeutic development. Recently, we have reported a Sanger method based genome sequence of a viral isolate named SARS-CoV-2 NIB-1, circulating in Bangladesh. The genome has four novel mutations in V121D, V843F, A889V and G1691C positions. V121D substitution has the potential to destabilize the Non-Structural Protein (NSP-1) which inactivates the type-1 Interferon-induced antiviral system hence this mutant could be the basis of attenuated vaccines against SARS-CoV-V843F, A889V and G1691C are all located in NSP3. G1691C can decrease the flexibility of the protein while V843F and A889V changed the binding pattern of SARS-CoV-2 Papain-Like protease (PLPro) inhibitor GRL0617. V843F PLPro showed reduced affinity for Interferon Stimulating Gene-15 (ISG-15) protein whereas V843F+A889V double mutants exhibited the same binding affinity as wild type PLPro. Here, V843F is a conserved position of PLPro that damaged the structure but A889V, a less conserved residue, most probably neutralized that damage. Mutants of NSP1 could provide attenuated vaccines against coronavirus. Also, these mutations of PLPro could be targeted to develop anti-SARS therapeutics.

scholarly journals Novel mutations in NSP-1 and PLPro of SARS-CoV-2 NIB-1 genome mount for effective therapeutics

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Mohammad Uzzal Hossain ◽  
Arittra Bhattacharjee ◽  
Md. Tabassum Hossain Emon ◽  
Zeshan Mahmud Chowdhury ◽  
Ishtiaque Ahammad ◽  
...  
Keyword(s):  
Nonstructural Protein ◽  
Etiologic Agent ◽  
Clinical Samples ◽  
Structural Protein ◽  
Synonymous Mutations ◽  
Viral Spread ◽  
Therapeutic Development ◽  
Interferon Stimulated Gene 15 ◽  
Conserved Residue

Abstract Background Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), is rapidly acquiring new mutations. Analysis of these mutations is necessary for gaining knowledge regarding different aspects of therapeutic development. Previously, we have reported a Sanger method-based genome sequence of a viral isolate named SARS-CoV-2 NIB-1, circulating in Bangladesh. The genome has four novel non-synonymous mutations in V121D, V843F, A889V, and G1691C positions. Results Using different computational tools, we have found V121D substitution has the potential to destabilize the non-structural protein-1 (NSP-1). NSP-1 inactivates the type-1 interferon-induced antiviral system. Hence, this mutant could be a basis of attenuated vaccines against SARS-CoV-2. V843F, A889V, and G1691C are all located in nonstructural protein-3 (NSP-3). G1691C can decrease the flexibility of the protein. V843F and A889V might change the binding pattern and efficacy of SARS-CoV-2 papain-like protease (PLPro) inhibitor GRL0617. V843F substitution in PLPro was the most prevalent mutation in the clinical samples. This mutation showed a reduced affinity for interferon-stimulated gene-15 protein (ISG-15) and might have an impact on innate immunity and viral spread. However, V843F+A889V double mutant exhibited the same binding affinity as wild type PLPro. A possible reason behind this phenomenon can be that V843F is a conserved residue of PLPro which damaged the protease structure, but A889V, a less conserved residue, presumably neutralized that damage. Conclusions Mutants of NSP-1 could provide attenuated vaccines against coronavirus. Also, these mutations of PLPro might be targeted to develop better anti-SARS therapeutics. We hope our study will help to get better insides during the development of attenuated vaccine and PLPro inhibitors.

scholarly journals Three New Mutations and Mild, Asymmetrical Phenotype in the Highly Distinctive LAMM Syndrome: A Report of Eight Further Cases

Genes ◽  
2019 ◽  
Vol 10 (7) ◽  
pp. 529
Author(s):  
Yassin ◽  
D’Arco ◽  
Morín ◽  
Pagarkar ◽  
Harrop-Griffiths ◽  
...  
Keyword(s):  
Inner Ear ◽  
Autosomal Recessive ◽  
Congenital Deafness ◽  
Novel Mutations ◽  
Recessive Condition ◽  
Autosomal Recessive Condition ◽  
New Mutations

Labyrinthine aplasia, microtia, and microdontia (LAMM) is an autosomal recessive condition causing profound congenital deafness, complete absence of inner ear structures (usually Michel’s aplasia), microtia (usually type 1) and microdontia. To date, several families have been described with this condition and a number of mutations has been reported. We report on eight further cases of LAMM syndrome including three novel mutations, c. 173T>C p.L58P; c. 284G>A p.(Arg95Gln) and c.325_327delinsA p.(Glu109Thrfs*18). Congenital deafness was the primary presenting feature in all affected individuals and consanguinity in all but two families. We compare the features in our patients to those previously reported in LAMM, and describe a milder, asymmetrical phenotype associated with FGF3 mutations.

scholarly journals Prevalence of, Antibody Response to, and Immunity Induced by Haemophilus ducreyi Hemolysin

1999 ◽  
Vol 67 (7) ◽  
pp. 3317-3328 ◽  
Author(s):  
Susan M. Dutro ◽  
Gwendolyn E. Wood ◽  
Patricia A. Totten
Keyword(s):  
Vaccine Development ◽  
Rabbit Model ◽  
Etiologic Agent ◽  
Haemophilus Ducreyi ◽  
Structural Protein ◽  
Wild Type ◽  
Ulcer Disease ◽  
A Cell

ABSTRACT Haemophilus ducreyi, the etiologic agent of chancroid, a genital ulcer disease, produces a cell-associated hemolysin whose role in virulence is not well defined. Hemolysin is encoded by two genes, hhdA and hhdB, which, based on their homology to Serratia marcescens shlA and shlBgenes, are believed to encode the hemolysin structural protein and a protein required for secretion and modification of this protein, respectively. In this study, we determined the prevalence and expression of the hemolysin genes in 90 H. ducreyi isolates obtained from diverse geographic locations from 1952 to 1996 and found that all strains contained DNA homologous to the hhdB andhhdA genes. In addition, all strains expressed a hemolytic activity. We also determined that hemolysin is expressed in vivo and is immunogenic, as indicated by the induction of antibodies to hemolysin in both the primate and rabbit disease models as well as in human patients with naturally acquired chancroid. Wild-type strain 35000 and isogenic hemolysin-negative mutants showed no difference in lesion development in the temperature-dependent rabbit model. However, immunization of rabbits with the purified hemolysin protein reduced the recovery of wild-type H. ducreyi, but not hemolysin-negative mutants, from lesions. Our study indicates that hemolysin is a possible candidate for vaccine development due to its immunogenicity, expression in vitro and in vivo by most, if not all, strains, and the effect of immunization on reducing the recovery of viable H. ducreyi in experimental disease in rabbits.

scholarly journals Aluminum-Marker of Wild Type 1 Poliovirus Strains

1970 ◽  
Vol 14 (5) ◽  
pp. 405-412
Author(s):  
Chieko Nakao ◽  
Isamu Tagaya ◽  
Toshihiko Komatsu ◽  
Hideo Kodama
Keyword(s):  
Wild Type

scholarly journals A Protein Antagonist of Activation-Induced Cytidine Deaminase Encoded by a Complex Mouse Retrovirus

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Gurvani B. Singh ◽  
Hyewon Byun ◽  
Almas F. Ali ◽  
Frank Medina ◽  
Dennis Wylie ◽  
...  
Keyword(s):  
Mouse Mammary Tumor Virus ◽  
Cytidine Deaminase ◽  
Wild Type ◽  
Mammary Tumor Virus ◽  
Mouse Mammary Tumor ◽  
Activation Induced Cytidine Deaminase ◽  
Immunodeficiency Virus ◽  
Tumor Virus ◽  
Hiv 1

ABSTRACT Complex human-pathogenic retroviruses cause high morbidity and mortality worldwide, but resist antiviral drugs and vaccine development due to evasion of the immune response. A complex retrovirus, mouse mammary tumor virus (MMTV), requires replication in B and T lymphocytes for mammary gland transmission and is antagonized by the innate immune restriction factor murine Apobec3 (mA3). To determine whether the regulatory/accessory protein Rem affects innate responses to MMTV, a splice-donor mutant (MMTV-SD) lacking Rem expression was injected into BALB/c mice. Mammary tumors induced by MMTV-SD had a lower proviral load, lower incidence, and longer latency than mammary tumors induced by wild-type MMTV (MMTV-WT). MMTV-SD proviruses had many G-to-A mutations on the proviral plus strand, but also C-to-T transitions within WRC motifs. Similarly, a lymphomagenic MMTV variant lacking Rem expression showed decreased proviral loads and increased WRC motif mutations relative to those in wild-type-virus-induced tumors, consistent with activation-induced cytidine deaminase (AID) mutagenesis in lymphoid cells. These mutations are typical of the Apobec family member AID, a B-cell-specific mutagenic protein involved in antibody variable region hypermutation. In contrast, mutations in WRC motifs and proviral loads were similar in MMTV-WT and MMTV-SD proviruses from tumors in AID-insufficient mice. AID was not packaged in MMTV virions. Rem coexpression in transfection experiments led to AID proteasomal degradation. Our data suggest that rem specifies a human-pathogenic immunodeficiency virus type 1 (HIV-1) Vif-like protein that inhibits AID and antagonizes innate immunity during MMTV replication in lymphocytes. IMPORTANCE Complex retroviruses, such as human-pathogenic immunodeficiency virus type 1 (HIV-1), cause many human deaths. These retroviruses produce lifelong infections through viral proteins that interfere with host immunity. The complex retrovirus mouse mammary tumor virus (MMTV) allows for studies of host-pathogen interactions not possible in humans. A mutation preventing expression of the MMTV Rem protein in two different MMTV strains decreased proviral loads in tumors and increased viral genome mutations typical of an evolutionarily ancient enzyme, AID. Although the presence of AID generally improves antibody-based immunity, it may contribute to human cancer progression. We observed that coexpression of MMTV Rem and AID led to AID destruction. Our results suggest that Rem is the first known protein inhibitor of AID and that further experiments could lead to new disease treatments.

Discovery of natural product ovalicin sensitive type 1 methionine aminopeptidases: molecular and structural basis

2019 ◽  
Vol 476 (6) ◽  
pp. 991-1003 ◽  
Author(s):  
Vijaykumar Pillalamarri ◽  
Tarun Arya ◽  
Neshatul Haque ◽  
Sandeep Chowdary Bala ◽  
Anil Kumar Marapaka ◽  
...  
Keyword(s):  
Natural Product ◽  
Active Site ◽  
Covalent Modification ◽  
Structural Basis ◽  
Wild Type ◽  
Methionine Aminopeptidases ◽  
Synthetic Derivative ◽  
Dynamics Simulations

Abstract Natural product ovalicin and its synthetic derivative TNP-470 have been extensively studied for their antiangiogenic property, and the later reached phase 3 clinical trials. They covalently modify the conserved histidine in Type 2 methionine aminopeptidases (MetAPs) at nanomolar concentrations. Even though a similar mechanism is possible in Type 1 human MetAP, it is inhibited only at millimolar concentration. In this study, we have discovered two Type 1 wild-type MetAPs (Streptococcus pneumoniae and Enterococcus faecalis) that are inhibited at low micromolar to nanomolar concentrations and established the molecular mechanism. F309 in the active site of Type 1 human MetAP (HsMetAP1b) seems to be the key to the resistance, while newly identified ovalicin sensitive Type 1 MetAPs have a methionine or isoleucine at this position. Type 2 human MetAP (HsMetAP2) also has isoleucine (I338) in the analogous position. Ovalicin inhibited F309M and F309I mutants of human MetAP1b at low micromolar concentration. Molecular dynamics simulations suggest that ovalicin is not stably placed in the active site of wild-type MetAP1b before the covalent modification. In the case of F309M mutant and human Type 2 MetAP, molecule spends more time in the active site providing time for covalent modification.

Blockage of angiotensin II type 1 receptor regulates TNF-α-induced MAdCAM-1 expression via inhibition of NF-κB translocation to the nucleus and ameliorates colitis

2010 ◽  
Vol 298 (2) ◽  
pp. G255-G266 ◽  
Author(s):  
Takashi Mizushima ◽  
Makoto Sasaki ◽  
Tomoaki Ando ◽  
Tsuneya Wada ◽  
Mamoru Tanaka ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Activity Index ◽  
Body Weight Loss ◽  
Disease Activity Index ◽  
Wild Type ◽  
Inflammatory Conditions ◽  
Tnf Α ◽  
Novel Target ◽  
Colitis Model

Mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) is an important target in the treatment of inflammatory bowel disease (IBD). Recently, treatment of IBD with an antibody to α4β7-integrin, a ligand for MAdCAM-1, has been an intense focus of research. Our aim was to clarify the mechanism by which MAdCAM-1 is regulated via angiotensin II type 1 receptor (AT1R), and to verify if AT1R might be a novel target for IBD treatment. The role of AT1R in the expression of MAdCAM-1 in SVEC (a murine high endothelial venule cell) and MJC-1 (a mouse colonic endothelial cell) was examined following cytokine stimulation. We further evaluated the effect of AT1R on the pathogenesis of immune-mediated colitis using AT1R-deficient (AT1R−/−) mice and a selective AT1R blocker. AT1R blocker significantly suppressed MAdCAM-1 expression induced by TNF-α, but did not inhibit phosphorylation of p38 MAPK or of IκB that modulate MAdCAM-1 expression. However, NF-κB translocation into the nucleus was inhibited by these treatments. In a murine colitis model induced by dextran sulfate sodium, the degree of colitis, judged by body weight loss, histological damage, and the disease activity index, was much milder in AT1R−/− than in wild-type mice. The expression of MAdCAM-1 was also significantly lower in AT1R−/− than in wild-type mice. These results suggest that AT1R regulates the expression of MAdCAM-1 under colonic inflammatory conditions through regulation of the translocation of NF-κB into the nucleus. Furthermore, inhibition of AT1R ameliorates colitis in a mouse colitis model. Therefore, AT1R might be one of new therapeutic target of IBD via regulation of MAdCAM-1.

scholarly journals Different Abilities of Escape Mutant-Specific Cytotoxic T Cells To Suppress Replication of Escape Mutant and Wild-Type Human Immunodeficiency Virus Type 1 in New Hosts

2007 ◽  
Vol 82 (1) ◽  
pp. 138-147 ◽  
Author(s):  
Mamoru Fujiwara ◽  
Junko Tanuma ◽  
Hirokazu Koizumi ◽  
Yuka Kawashima ◽  
Kazutaka Honda ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Escape Mutant ◽  
Wild Type ◽  
Specific Ctls ◽  
Immunodeficiency Virus ◽  
New Hosts ◽  
Hiv 1 ◽  
Hla Molecules

ABSTRACT There is much evidence that in human immunodeficiency virus type 1 (HIV-1)-infected individuals, strong cytotoxic T lymphocyte (CTL)-mediated immune pressure results in the selection of HIV-1 mutants that have escaped from wild-type-specific CTLs. If escape mutant-specific CTLs are not elicited in new hosts sharing donor HLA molecules, the transmission of these mutants results in the accumulation of escape mutants in the population. However, whether escape mutant-specific CTLs are definitively not elicited in new hosts sharing donor HLA molecules still remains unclear. A previous study showed that a Y-to-F substitution at the second position (2F) of the Nef138-10 epitope is significantly detected in HLA-A*2402+ hemophilic donors. Presently, we confirmed that this 2F mutant was an escape mutant by demonstrating strong and weak abilities of Nef138-10-specific CTL clones to suppress replication of the wild-type and 2F mutant viruses, respectively. We demonstrated the existence of the 2F-specific CTLs in three new hosts who had been primarily infected with the 2F mutant. The 2F-specific CTL clones suppressed the replication of both wild-type and mutant viruses. However, the abilities of these clones to suppress replication of the 2F virus were much weaker than those of wild-type-specific and the 2F-specific ones to suppress replication of the wild-type virus. These findings indicate that the 2F mutant is conserved in HIV-1-infected donors having HLA-A*2402, because the 2F-specific CTLs failed to completely suppress the 2F mutant replication and effectively prevented viral reversion in new hosts carrying HLA-A*2402.

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