Antiviral Antibiotics Research Articles

Cell Surface B2m-Free Human Leukocyte Antigen (HLA) Monomers and Dimers: Are They Neo-HLA Class and Proto-HLA?

Cell surface HLA-I molecules (Face-1) consist of a polypeptide heavy chain (HC) with two groove domains (G domain) and one constant domain (C-domain) as well as a light chain, B2-microglobulin (B2m). However, HCs can also independently emerge unfolded on the cell surface without peptides as B2m-free HC monomers (Face-2), B2m-free HC homodimers (Face 3), and B2m-free HC heterodimers (Face-4). The transport of these HLA variants from ER to the cell surface was confirmed by antiviral antibiotics that arrest the release of newly synthesized proteins from the ER. Face-2 occurs at low levels on the normal cell surface of the lung, bronchi, epidermis, esophagus, breast, stomach, ilium, colorectum, gall bladder, urinary bladder, seminal vesicles ovarian epithelia, endometrium, thymus, spleen, and lymphocytes. They are upregulated on immune cells upon activation by proinflammatory cytokines, anti-CD3 antibodies, antibiotics (e.g., ionomycin), phytohemagglutinin, retinoic acid, and phorbol myristate acetate. Their density on the cell surface remains high as long as the cells remain in an activated state. After activation-induced upregulation, the Face-2 molecules undergo homo- and hetero-dimerization (Face-3 and Face-4). Alterations in the redox environment promote dimerization. Heterodimerization can occur among and between the alleles of different haplotypes. The glycosylation of these variants differ from that of Face-1, and they may occur with bound exogenous peptides. Spontaneous arthritis occurs in HLA-B27+ mice lacking B2m (HLA-B27+ B2m-/-) but not in HLA-B27+ B2m+/- mice. The mice with HLA-B27 in Face-2 spontaneous configuration develop symptoms such as changes in nails and joints, hair loss, and swelling in paws, leading to ankyloses. Anti-HC-specific mAbs delay disease development. Some HLA-I polyreactive mAbs (MEM series) used for immunostaining confirm the existence of B2m-free variants in several cancer cells. The upregulation of Face-2 in human cancers occurs concomitantly with the downregulation of intact HLAs (Face-1). The HLA monomeric and dimeric variants interact with inhibitory and activating ligands (e.g., KIR), growth factors, cytokines, and neurotransmitters. Similarities in the amino acid sequences of the HLA-I variants and HLA-II β-chain suggest that Face-2 could be the progenitor of both HLA classes. These findings may support the recognition of these variants as a neo-HLA class and proto-HLA.

The Role of Molecular Modeling and Bioinformatics in Treating a Pandemic Disease: The Case of COVID-19

The COVID-19 pandemic first appeared in Wuhan, China, in December 2019 in a cluster of pneumonia patients. The causative agent was found to be SARS-CoV-2. Here, we are summarizing current treatment strategies and highlighting the role of bioinformatics, molecular modeling, and structural biology during the COVID-19 pandemic. There are different pharmacological treatments, mostly repurposed drugs, employed for the treatment of COVID-19, including antiviral drugs, corticosteroids, biologic drugs, antibiotics, antifungal agents, and anticoagulants. Some immune-based therapies are also under evaluation, including convalescent plasma, IL-1, IL-6 inhibitors, and interferons. Different bioinformatics networks are established to provide information about the structure, transcriptome, and pathogenicity of the virus. The genotyping analysis for SARS-CoV-2 is also useful in identifying different mutations, SNPs, and conservative domains along the viral genome. Cryo-EM and X-ray diffraction had a crucial role in determining the structure of viral proteins such as spike (S) protein, main protease, and RdRp. NMR had a minor role and determining the structure of nucleocapsid (N) protein only. Several docking studies were performed to predict the interaction of certain FDA-approved drugs with known efficacy and toxicity, while others used natural products. Among different study types, in silico drug prediction and repurposing have the lowest risk with less off-target results. Therefore, bioinformatics and in silico studies have an important role during pandemics in providing information about viral structure and function and predicting potential treatments.

Current Potential Therapeutic Approaches against SARS-CoV-2: A Review.

The ongoing SARS-CoV-2 pandemic is a serious threat to public health worldwide and, to date, no effective treatment is available. Thus, we herein review the pharmaceutical approaches to SARS-CoV-2 infection treatment. Numerous candidate medicines that can prevent SARS-CoV-2 infection and replication have been proposed. These medicines include inhibitors of serine protease TMPRSS2 and angiotensin converting enzyme 2 (ACE2). The S protein of SARS-CoV-2 binds to the receptor in host cells. ACE2 inhibitors block TMPRSS2 and S protein priming, thus preventing SARS-CoV-2 entry to host cells. Moreover, antiviral medicines (including the nucleotide analogue remdesivir, the HIV protease inhibitors lopinavir and ritonavir, and wide-spectrum antiviral antibiotics arbidol and favipiravir) have been shown to reduce the dissemination of SARS-CoV-2 as well as morbidity and mortality associated with COVID-19.

THERAPEUTIC MANAGEMENT OF PATIENTS INFECTED WITH SARS-CoV-2 VIRUS - A REVIEW

INTRODUCTION: Due to the rapid outbreak of the pandemic that causes SARS-CoV-2 infection and the increased rate of morbidity and mortality as a result of this new infection, the treatments pursued in therapy must have an increased potential to inhibit the replication of this virus.
 OBJECTIVES: The main objective of this article was to describe the most current drug therapies and their mechanisms of action used in the treatment of COVID-19. In this article, we have collected the latest information and multilingual international scientific discoveries about the treatment of COVID-19.
 RESULTS: Several compounds can be used to treat COVID-19 in order to reduce the duration of the disease and the rate of infection, to reduce the viral load, to prevent tissue damage, to stimulate the maturation of many cells, including immune cells in the human body and to reduce its severe symptoms. The most effective treatments were based on the antiviral drugs, antimalarial drugs, anti-inflammatory drugs, analgesics drugs, glycopeptide antibiotics, anticoagulants, vitamin C and vitamin D. The simplest and most direct approach to controlling SARS-CoV-2 outbreaks is the use of passive antibodies transferred from plasma to convalescent patients. Recently, studies have been completed for several vaccines that are approved against SARS-CoV-2.
 CONCLUSION: Scientists around the world are collaborating and innovating to make tests, treatments and vaccines available to the public that will save lives collectively and end this pandemic.

New Viral Infection COVID-19: Current Status, Challenges and Possible Treatments

Since December 2019, the prevalence of novel coronavirus infection (named as COVID- 19 by WHO on Feb 11, 2020) has become a growing healthcare concern worldwide. On March 11, 2020, the WHO declared COVID-19 a global pandemic. As no specific approved treatment options are available for the COVID-19 infection, several existing antiviral drugs in combination with others have become the mainstay therapy. The targets for the treatment of the infection include viral targets such as polymerases, spike glycoproteins, membrane proteins, and viral envelope and host targets such as host proteases and host receptors. Antiviral agents, immunomodulatory agents, and empiric broad-spectrum antibiotics can be used as treatment therapies for the infection. Convalescent plasma therapy has also been proposed as an effective treatment for COVID-19. Additionally, many studies are ongoing to develop a potent and effective vaccine that completely blocks SARS-CoV-2. Nevertheless, prevention of spread of the virus remains the first and foremost step towards controlling and managing the coronavirus infection.

P0240ACQUIRED THROMBOTIC THROMBOCYTOPENIC PURPURA IN HIV POSITIVE PATIENTS SUCCESSFULLY TREATED WITH CAPLACIZUMAB: ABOUT TWO CASES

Abstract Background and Aims Acquired thrombotic thrombocytopenic purpura (aTTP) is a thrombotic microangiopathy still nowadays associated with a high risk of death. Standards of care included at first the association of plasmatic exchanges, Rituximab and steroids. The emergence of Caplacizumab, a nanobody targeting the A1 receptor of Von Willebrand Factor (VWF), significantly changed the prognosis of the disease. Thrombocytopenia is frequent in HIV positive patients, and aTTP is frequently considered. Prevalence of HIV positive in aTTP patients ranges from less than 1% in western countries, up to more than 50% in African countries. The pathophysiology still remains partially understood, leading to the development of autoantibodies targeting the ADAMTS13 metalloprotease. For now, no specific recommendations are available, and standards of care consist in treating HIV positive patient the same as other aTTP patients. We present the first description of two HIV positive patients, successfully treated with caplacizumab. Method We report there two cases of black women, respectively aged 31 (Patient 1) and 52 years old (Patient 2), both positive for HIV for several years. The first one had stopped any antiviral treatment few months ago, and had a positive blood viral load of 110764 copies/ml. Her CD4+ rate was 30/mm3. The second one was under antiviral medication, with a negative viral load and a CD4+ rate of 295/mm3. Both were admitted in our department because of low platelet levels and hemolysis, associated with inflammatory triggers. Bacteriema for Streptococcus mitis was discovered on admission in Patient 1 and Patient 2, who had a long-term follow-up for Still disease, presented with a flare-up. Results Both patients had positive anti-ADAMTS13 autoantibodies (Patient 1: titer 42 UI/ml, Patient 2: 45 UI/ml), with undetectable ADAMTS-13 activities. They were treated with plasmatic exchanges until platelets levels reached over 150 G/L, steroids 1.5 mg/kg/j, Rituximab 375 mg/m2 at day 1, 4 and 8 and finally caplacizumab 10 mg before the 2nd plasmatic exchange and every day until the ADAMTS13 activity reached over 20%. Antiviral therapy and antibiotics were initiated in Patient 1 and antiviral therapy was maintained in Patient 2. The evolution was promptly favorable with normalization of platelets levels at Day 4 in Patient 1, and Day 15 in Patient 2. Patient 1 stopped caplacizumab at Day 12 and Patient 2 at day 17, when ADAMTS 13 reached over 20%. None of them relapsed after treatment, with a respective follow-up of 4 and 2 months. Conclusion Caplacizumab seems to be a safe and efficient treatment for aTTP in HIV positive patients.

Complete Genome Sequence of Actinomadura Parvosata Subsp. Kistnae, A Rich Source of Novel Natural Product (Bio-)Chemistry.

The soil dwelling actinomycete strain Actinomadura parvosata subsp. kistnae is the producer of the antiviral antibiotics kistamicin A and B. Genome sequencing and bioinformatic analysis revealed the presence of the kistamycin biosynthetic gene cluster responsible for the formation of these non-ribosomal peptides as well as an impressive number of yet uncharacterized biosynthetic pathways. This includes polyketide, ribosomal and non-ribosomal peptide and a large number of terpenoid biosynthetic loci encoding yet unknown natural products. The genomic data of this strain is thus a treasure trove for genome mining for novel functional metabolites and new biocatalysts.

Molecular orbital studies on nucleoside antibiotics. VI. Conformation of 5-vinyl- and 5-ethynyl-2′-deoxyuridines

PCILO computations have been carried out on the conformation of two potential antiviral nucleoside antibiotics, namely, 5-vinyl- and 5-ethynyl-2'-deoxyuridines, along with the parent nucleoside 5-methyl-2'-deoxyuridine (thymidine). The results indicate that the preferred conformation for all three molecules is syn (XCN = 240° for 5-vinyl- and 5-methyl-2'-deoxyuridine and 210°-240° for 5'-ethyl-2'-deoxyuridine) when an intramolecular hydrogen bonding possibility between the sugar and the base is allowed. The conformation around the exocyclic C(4')-C(5') bond is gt for the first two molecules, while for the third it is gg. However, in the absence of an intramolecular hydrogen bonding possibility, both nucleoside antibiotics as well as the parent nucleoside have strikingly similar preference for the anti-gg conformation. The biological implication of this similarity in terms of the mechanism of action of the two nucleoside antibiotics is discussed.

Use of Drotrecogin Alfa (Activated) in a Severe Acute Respiratory Syndrome Patient with Severe Sepsis

Use of Drotrecogin Alfa (Activated) in a Severe Acute Respiratory Syndrome Patient with Severe Sepsis

Donor Lymphocytes Stimulated with CMV pp65 Gene Modified Dendritic Cells for Prophylaxis of CMV Following Allogeneic Haemopoietic Stem Cell Transplantation.

Background: Cytomegalovirus (CMV) reactivation post-allogeneic haemopoietic stem cell transplant (HSCT) causes morbidity and mortality. Pharmacological therapy is limited by bone marrow suppression that can result in opportunistic infection. Adoptive transfer of ex-vivo generated CMV-specific T-cells has the potential to rapidly restore immunity, prevent CMV infection and circumvent the need for pharmacotherapy.Methods: We have recruited 18 patients into a trial of donor-derived CMV-specific T-cells generated using dendritic cells transduced with a fiber modified adenoviral vector encoding the immunodominant CMV matrix protein pp65. Thus far, 8 patients have received T-cells prophylactically starting at day 28 post-HSCT. Recipients were monitored for adverse reactions, CMV reactivation by polymerase chain reaction (PCR) and CMV-specific immune reconstitution.Results: 18 cultures have been completed with an 8.5–30 fold increase in total cell number (mean 2.1 × 108, range 0.8–5.1 × 108). Products consisted of T-cells (median 96.5%) displaying an effector memory phenotype (CD45RO+, CD62L−) and a predominance of CD8+ (14–90%) over CD4+ (2.5–57%) cells. All cultures exhibited negligible alloreactivity against recipient derived targets (0–3.6% specific lysis at E:T ratio of 20:1) but strong killing of CMV pp65 peptide pulsed targets (43–79% specific lysis at E:T 20:1). Killing was also observed against targets labeled with adenoviral antigens (2.7–12.5% lysis at E:T 20:1) demonstrating the bi-virus specificity of these cultures. In HLA-B7 and HLA-A2 donors, percentages of tetramer binding T-cells accounted for 3.2 to 40% of cells. Enrichment of cells recognizing known HLA-A24, B8 and B35 epitopes was not observed despite these cultures exhibiting strong cytotoxic activity against pp65 pulsed targets. Reasons for non-infusion include early death post-transplant (3 patients), failure of cultures to meet release criteria (2 patients), severe graft versus host disease (1 patient) and refusal (1 patient). 3 patients are currently awaiting infusion. Patients infused have been followed from 21 to 189 days post infusion. In 5 patients we have demonstrated rapid, polyepitope, CMV pp65-specific immune reconstitution using tetramer and ELISPOT analysis. CMV reactivation by PCR has occurred in 3 patients but none have progressed to CMV disease, suggesting the functional capacity of the cells to control viral reactivation. One patient received pharmacotherapy with valaciclovir while no other patients have required anti-viral antibiotics. There have been no infusion related adverse reactions. Graft versus host disease, non-CMV infections and other adverse events have not exceeded expected rates.Conclusions: Prophylactic adoptive transfer of CMV-specific T-cells is safe, hastens CMV-specific immune reconstitution and may reduce the need for anti-CMV pharmacotherapy in allogeneic HSCT recipients. Our data indicate the potential of specific cellular therapy to control opportunistic infections in severely immunosuppressed patients post-HSCT.

Metabolites Produced by Actinomycetes — Antiviral Antibiotics and Enzyme Inhibitors

AbstractFor Abstract see ChemInform Abstract in Full Text.

Fattiviracins, Antiviral Antibiotics Produced by an Actinomycete

Fattiviracins, Antiviral Antibiotics Produced by an Actinomycete

Ring‐Expanded (“Fat”) Nucleosides as Broad‐Spectrum Anticancer and Antiviral Agents

AbstractFor Abstract see ChemInform Abstract in Full Text.

Fattiviracins, Antiviral Antibiotics Produced by an Actinomycete

In 1995, we discovered new antiherpetic antibiotics, called fattiviracins. The producing organism was classified as a strain belonging to Streptomyces microflavus. The strain produced at least 13 fattiviracin derivatives (FV-1 to FV-13). Fattiviracins were obtained as a white amorphous powder, and their molecular weights are in the range of 1400 to 1500. They are readily soluble in water, methanol, pyridine and DMSO, but insoluble in other organic solvents. Fattiviracins have macrocyclic diesters formed by the binding of two trihydroxy fatty acids and two D-glucose residues in the molecule, and they can be divided into 5 families, according to the length of fatty acid moiety. Fattiviracins have a potent activity against enveloped DNA viruses such as the herpes family, HSV-1 and VZV and enveloped RNA viruses such as influenza A and B viruses, and three strains of HIV-1, in the order of a few μg/ml of EC50. The biosynthetic pathway of fattiviracins is also becoming clearer. Using bacitracin-resistant strains, enhanced and astringent production of fattiviracin was recognized: fattiviracin FV-13, having the longest fatty acid chains in the molecule was dramatically enhanced by a C55-isoprenyl phosphate metabolism.

Ring-expanded ("Fat") nucleosides as broad-spectrum anticancer and antiviral agents.

Ring-expanded (ldauo;fat") nucleosides (RENs) described in this review are analogues of purine nucleosides containing a 5:7-fused imidazodiazepine or imidazotriazepine ring system. They are both of natural and synthetic origin, and are of chemical, biochemical, biophysical, as well as medicinal interest. The important natural RENs include coformycin, pentostatin, azepinomycin, adechlorin, and adecypenol. A majority of them are synergistic antitumor and/or antiviral antibiotics which potentiate the effects of other antitumor or antiviral compounds through inhibition of key enzymes such as adenosine deaminase or guanase which would otherwise metabolically degrade the active compounds into therapeutically less potent or totally inactive counterparts. However, despite the fact that some of the natural RENs such as coformycins are the strongest known enzyme inhibitors, they have not been proven as effective clinically as anticipated because of the extremely high toxicity associated with their use. Nevertheless, pentostatin (2'-deoxycoformycin) is a conspicuous exception as it is gaining wide attention in recent years as a clinically effective therapeutic agent against leukemias and lymphomas. Many of the recently reported synthetic RENs, by contrast, possess biological activities of their own, in particular against a wide spectrum of cancers and viruses with little toxicity to the host cells, and thus hold considerable promise as chemotherapeutic agents. The promising preliminary in vitro data concerning the effects of RENs on human cancers, in particular prostate and breast cancer cells, support their further pursuit in animal and clinical studies. RENs also carry promise against many viral infections belonging to the families of hepatitis, herpes, and respiratory infections, most notable being the hepatitis B (HBV), hepatitis C (HCV), and the West Nile (WNV) viruses.

Structures of Fattiviracin Family, Antiviral Antibiotics.

Structures of Fattiviracin Family, Antiviral Antibiotics.

Synthesis and antiviral activity of alkylphosphonic acid derivatives of oxetanocin-A

A series of phosphonoalkyl derivatives of antiviral antibiotics oxetanocin-A 2 were synthesized and tested in vitro for anti-HSV-1, HSV-2, and anti-HIV-1 activity.

New antiviral antibiotics, kistamicins A and B. I. Taxonomy, production, isolation, physico-chemical properties and biological activities.

A new strain of Microtetraspora parvosata subsp. kistnae subsp. nov. (ATCC 55076) was found to produce new antiviral antibiotics, designated kistamicins A and B. These antibiotics exhibited activity against influenza virus type A and moderate activity against Gram-positive bacteria.

New antiviral antibiotics, kistamicins A and B. II. Structure determination.

The structures of antiviral antibiotics kistamicins A and B have been determined by a combination of chemical degradation and spectral analysis. They are commonly composed of D-tyrosine, 3,5-dihydrophenylglycine, a biphenyl ether bis-amino acid, and a diphenyl substituted indole tris-amino acid, forming a tricyclic ring structure. Kistamicin B possessed a phenethylamide at the amino terminal of kistamicin A. They are structurally related to the nuclei of the vancomycin group antibiotics particularly to antibiotic complestatin.

New antiviral antibiotics, cycloviracins B1 and B2. I. Production, isolation, physico-chemical properties and biological activity.

Kibdelosporangium albatum No. R761-7 (ATCC 55061) produced new antiviral antibiotics, cycloviracins B1 and B2. They show weak activity against Gram-positive bacteria and potent antiviral activity against herpes simplex virus type 1. Unique acylsaccharide structures were established for cycloviracins B1 and B2 by degradation and spectroscopic analysis.