ABSTRACT
We recently developed compound FC-7269 for targeting the Molluscum contagiosum virus processivity factor (mD4) and demonstrated its ability to inhibit viral processive DNA synthesis in vitro and cellular infection of an mD4-dependent virus (Antiviral Res 211, 2023,105520). However, despite a thorough medicinal chemistry campaign we were unable to generate a potent second analog as a requisite for drug development. We overcame this impasse, by conjugating a short hydrophobic trivaline peptide to FC-7269 to produce FC-TriVal-7269 which significantly increased antiviral potency and reduced cellular toxicity.
Subject(s)
Antiviral Agents , Molluscum contagiosum virus , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/chemical synthesis , Molluscum contagiosum virus/drug effects , Humans , Virus Replication/drug effects , Molluscum Contagiosum/drug therapy , Oligopeptides/pharmacology , Oligopeptides/chemistry , Animals , Cell LineSubject(s)
Administration, Topical , Linoleic Acids/pharmacology , Molluscum Contagiosum/drug therapy , Molluscum contagiosum virus/drug effects , Plant Oils/pharmacology , Skin/pathology , gamma-Linolenic Acid/pharmacology , Child , Child, Preschool , Female , Follow-Up Studies , Humans , Linoleic Acids/administration & dosage , Linoleic Acids/therapeutic use , Male , Molluscum Contagiosum/pathology , Molluscum Contagiosum/virology , Molluscum contagiosum virus/isolation & purification , Oenothera biennis , Outcome Assessment, Health Care , Plant Oils/administration & dosage , Plant Oils/therapeutic use , Skin/virology , gamma-Linolenic Acid/administration & dosage , gamma-Linolenic Acid/therapeutic useABSTRACT
Biodiversity of the marine world is only partially subjected to detailed scientific scrutiny in comparison to terrestrial life. Life in the marine world depends heavily on marine fungi scavenging the oceans of lifeless plants and animals and entering them into the nutrient cycle by. Approximately 150 to 200 new compounds, including alkaloids, sesquiterpenes, polyketides, and aromatic compounds, are identified from marine fungi annually. In recent years, numerous investigations demonstrated the tremendous potential of marine fungi as a promising source to develop new antivirals against different important viruses, including herpes simplex viruses, the human immunodeficiency virus, and the influenza virus. Various genera of marine fungi such as Aspergillus, Penicillium, Cladosporium, and Fusarium were subjected to compound isolation and antiviral studies, which led to an illustration of the strong antiviral activity of a variety of marine fungi-derived compounds. The present review strives to summarize all available knowledge on active compounds isolated from marine fungi with antiviral activity.
Subject(s)
Antiviral Agents/isolation & purification , Aquatic Organisms/chemistry , Fungi/chemistry , Animals , Antiviral Agents/pharmacology , HIV/drug effects , Humans , Molluscum contagiosum virus/drug effects , Orthomyxoviridae/drug effects , Porcine respiratory and reproductive syndrome virus/drug effects , Respiratory Syncytial Viruses/drug effects , Simplexvirus/drug effects , Tobacco Mosaic Virus/drug effectsSubject(s)
Anti-Bacterial Agents/therapeutic use , Disease Management , Molluscum Contagiosum/drug therapy , Molluscum contagiosum virus/drug effects , Practice Guidelines as Topic , Adolescent , Contact Tracing , Female , HIV Infections/prevention & control , Humans , Male , Molluscum contagiosum virus/isolation & purification , Reproductive Health/standards , United KingdomABSTRACT
The dermatological disease molluscum contagiosum (MC) presents as lesions restricted solely to the skin. The poxvirus molluscum contagiosum virus (MCV) is responsible for this skin disease that is easily transmitted through casual contact among all populations, with greater frequency in children and immunosuppressed individuals. In addition, sexual transmission of MCV in adolescents and adults is a health concern. Although the skin lesions ultimately resolve in immunocompetent individuals, they can persist for extended periods, be painful, and result in scarring. Treatment is problematic, and there is no drug that specifically targets MCV. The inability of MCV to propagate in cell culture has impeded drug development. To overcome these barriers, we integrated three new developments. First, we identified a new MCV drug target (mD4) that is essential for processive DNA synthesis in vitro. Second, we discovered a small chemical compound that binds to mD4 and prevents DNA synthesis in vitro. Third, and most significant, we engineered a hybrid vaccinia virus (mD4-VV) in which the natural vaccinia D4 (vD4) gene is replaced by the mD4 target gene. This hybrid virus is dependent on mD4 for viral growth in culture and is inhibited by the small compound. This target system provides, for the first time, a platform and approach for the discovery and evaluation of new therapeutics that can be used to treat MC.
Subject(s)
DNA, Viral , DNA-Directed DNA Polymerase/genetics , Molluscum contagiosum virus/genetics , Reassortant Viruses/genetics , Viral Proteins/genetics , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Biological Assay , Cell Line , Chlorocebus aethiops , Cloning, Molecular , DNA-Directed DNA Polymerase/metabolism , Drug Discovery , Epithelial Cells/drug effects , Epithelial Cells/pathology , Epithelial Cells/virology , Gene Expression , Humans , Kidney/drug effects , Kidney/pathology , Kidney/virology , Molecular Targeted Therapy , Molluscum contagiosum virus/drug effects , Molluscum contagiosum virus/metabolism , Plasmids/chemistry , Plasmids/metabolism , Rabbits , Reassortant Viruses/drug effects , Reassortant Viruses/metabolism , Recombinant Proteins , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Vaccinia virus/drug effects , Vaccinia virus/genetics , Vaccinia virus/metabolism , Viral Proteins/antagonists & inhibitors , Viral Proteins/metabolismABSTRACT
CMX001 (hexadecyloxypropyl-cidofovir, Brincidofovir) is a broad spectrum, lipid conjugate of cidofovir that is converted intracellularly into the active antiviral, cidofovir diphosphate. The lipid conjugation results in oral bioavailability, higher intracellular concentrations of active drug, lower plasma concentrations of cidofovir and increased antiviral potency against dsDNA viruses.
Subject(s)
Antiviral Agents/therapeutic use , Cytosine/analogs & derivatives , DNA Virus Infections/drug therapy , Organophosphonates/therapeutic use , Adenoviridae/drug effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cytomegalovirus/drug effects , Cytosine/chemistry , Cytosine/pharmacology , Cytosine/therapeutic use , Humans , Microbial Sensitivity Tests , Molluscum contagiosum virus/drug effects , Organophosphonates/chemistry , Organophosphonates/pharmacology , Orthopoxvirus/drug effects , Polyomavirus/drug effectsABSTRACT
Molluscum contagiosum is a common self-limited viral skin infection. The course of the infection often includes tender, crusted, erythematous lesions that prompt suspicion for bacterial infection. However, these signs of inflammation represent a host response that often precedes resolution of the viral disease, rather than bacterial superinfection, and do not require additional antibacterial treatment. We present a case report and retrospective review of 7 additional cases to characterize the clinical presentation of inflamed molluscum, assess the utilization of medical resources, and consider the psychosocial burden associated with mistaken diagnoses of bacterial infection. We propose the acronym "BOTE"* sign (for beginning of the end) to help underscore the significance of inflammation as an expected variant in the evolution of molluscum immunity.
Subject(s)
Molluscum Contagiosum/diagnosis , Molluscum Contagiosum/drug therapy , Molluscum contagiosum virus/isolation & purification , Adolescent , Anti-Bacterial Agents/therapeutic use , Child , Child, Preschool , Dermatologic Agents/therapeutic use , Emergency Service, Hospital , Female , Follow-Up Studies , Humans , Male , Molluscum contagiosum virus/drug effects , Predictive Value of Tests , Remission, Spontaneous , Risk Assessment , Severity of Illness Index , Treatment Outcome , United StatesSubject(s)
Immunoglobulin G/adverse effects , Immunosuppressive Agents/adverse effects , Molluscum Contagiosum/chemically induced , Molluscum contagiosum virus/drug effects , Papillomavirus Infections/drug therapy , Adult , Antibodies, Monoclonal/therapeutic use , Arthritis, Psoriatic/drug therapy , Etanercept , Female , Humans , Immunoglobulin G/therapeutic use , Immunosuppressive Agents/therapeutic use , Infliximab , Molluscum Contagiosum/immunology , Papillomavirus Infections/pathology , Psoriasis/drug therapy , Receptors, Tumor Necrosis Factor/therapeutic use , Recurrence , Tumor Necrosis Factor-alpha/antagonists & inhibitorsSubject(s)
Antiviral Agents/pharmacology , Cytosine/analogs & derivatives , DNA-Directed DNA Polymerase/metabolism , Molluscum Contagiosum/drug therapy , Molluscum contagiosum virus/drug effects , Organophosphonates/pharmacology , Cidofovir , Cytosine/pharmacology , Humans , Molluscum Contagiosum/virology , Molluscum contagiosum virus/geneticsSubject(s)
Adjuvants, Immunologic/therapeutic use , Aminoquinolines/therapeutic use , Molluscum Contagiosum/drug therapy , Administration, Topical , Follow-Up Studies , Humans , Imiquimod , Immunity, Innate/drug effects , Keloid/drug therapy , Molluscum contagiosum virus/drug effects , Papillomaviridae/drug effects , Papillomavirus Infections/drug therapy , Pilot Projects , Recurrence , Warts/drug therapyABSTRACT
We have developed microtiter assays for detecting catalysis by type IB topoisomerases and retroviral integrases. Each assay employs model DNA substrates containing biotin in one strand and digoxigenin in another. In each case action of the enzyme results in the formation of a single DNA strand containing both groups. This allows the reaction product to be quantified by capturing biotinylated product DNA on avidin-coated plates followed by detection using an anti-digoxigenin ELISA. The order of addition of reactants and inhibitors can be varied to distinguish effects of test compounds on different steps in the reaction. These assays were used to screen compound libraries for inhibitors active against mammalian topoisomerase or HIV integrase. We identified (-)-epigallocatechin 3-O:-gallate, as a potent inhibitor of religation by mammalian topoisomerase (IC(50) of 26 nM), potentially explaining the anti-cancer properties previously attributed to this compound. New integrase inhibitors were also identified. A similar strategy may be used to develop microtiter assays for many further DNA modifying enzymes.
Subject(s)
Catechin/analogs & derivatives , Drug Evaluation, Preclinical/methods , Enzyme Inhibitors/isolation & purification , HIV Integrase/metabolism , HIV-1/enzymology , Molluscum contagiosum virus/enzymology , Topoisomerase I Inhibitors , Animals , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Avidin/metabolism , Base Sequence , Biotinylation , Catalysis , Catechin/isolation & purification , Catechin/pharmacology , DNA Topoisomerases, Type I/classification , DNA Topoisomerases, Type I/metabolism , Enzyme Inhibitors/pharmacology , Enzyme-Linked Immunosorbent Assay/methods , HIV Integrase Inhibitors/isolation & purification , HIV Integrase Inhibitors/pharmacology , HIV-1/drug effects , Inhibitory Concentration 50 , Molluscum contagiosum virus/drug effects , Reproducibility of Results , Time FactorsABSTRACT
Molluscum contagiosum virus (MCV) and variola virus (VAR) are the only two poxviruses that are specific for man. MCV causes skin tumors in humans and primarily in children and immunocompromised individuals. MCV is unable to replicate in tissue culture cells or animals. Recently, the DNA sequence of the 190 kbp MCV genome was reported by Senkevich et al. MCV was predicted to encode 163 proteins of which 103 were clearly related to those of smallpox virus. In contrast, it was found that MCV lacks 83 genes of VAR, including those involved in the suppression of the host response to infection, nucleotide biosynthesis, and cell proliferation. However, MCV possesses 59 genes predicted to code for novel proteins including MHC-class I, chemokine and glutathione peroxidase homologs not found in other poxviruses. The MCV genomic data allow the investigation of novel host defense mechanisms and provide new possibilities for the development of therapeutics for treatment and prevention of the MCV infection.