Sangivamycin (S) is an adenosine (A) nucleoside analog with low nanomolar antiviral activity against SARS-CoV-2 in vitro. Previously, low nanomolar antiviral efficacy was revealed when tested against multiple viral variants in several cell types. SARS-CoV-2 RNA isolated from live virus infected cells and the virions released from these cells was analyzed by mass spectrometry (MS) for S incorporation.
View Article and Find Full Text PDFSangivamycin is a nucleoside analog that is well tolerated by humans and broadly active against phylogenetically distinct viruses, including arenaviruses, filoviruses, and orthopoxviruses. Here, we show that sangivamycin is a potent antiviral against multiple variants of replicative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with half-maximal inhibitory concentration in the nanomolar range in several cell types. Sangivamycin suppressed SARS-CoV-2 replication with greater efficacy than remdesivir (another broad-spectrum nucleoside analog).
View Article and Find Full Text PDFRNA represents a potential target for new antiviral therapies, which are urgently needed to address public health threats such as the human immunodeficiency virus (HIV). We showed previously that the interaction between the viral Tat protein and the HIV-1 trans-activation response (TAR) RNA was blocked by TB-CP-6.9a.
View Article and Find Full Text PDFFiloviruses, such as Ebola virus and Marburg virus, are of significant human health concern. From 2013 to 2016, Ebola virus caused 11,323 fatalities in Western Africa. Since 2018, two Ebola virus disease outbreaks in the Democratic Republic of the Congo resulted in 2354 fatalities.
View Article and Find Full Text PDFThe DNA mutagenic enzyme known as APOBEC3G (A3G) plays a critical role in innate immunity to Human Immunodeficiency Virus-1 (HIV-1 ). A3G is a zinc-dependent enzyme that mutates select deoxycytidines (dC) to deoxyuridine (dU) through deamination within nascent single stranded DNA (ssDNA) during HIV reverse transcription. This activity requires that the enzyme be delivered to viral replication complexes by redistributing from the cytoplasm of infected cells to budding virions through what appears to be an RNA-dependent process.
View Article and Find Full Text PDFThe infectivity of HIV depends on overcoming APOBEC3 (A3) innate immunity, predominantly through the expression of the viral protein Vif, which induces A3 degradation in the proteasome. Disruption of the functional interactions of Vif enables A3 mutagenesis of the HIV genome during viral replication, which can result in a broadly neutralizing antiviral effect. Vif function requires self-association along with interactions with A3 proteins, protein chaperones, and factors of the ubiquitination machinery and these are described here as a potential platform for novel antiviral drug discovery.
View Article and Find Full Text PDFThe HIV-1 frameshift-stimulating (FSS) RNA, a regulatory RNA of critical importance in the virus' life cycle, has been posited as a novel target for anti-HIV drug development. We report the synthesis and evaluation of triazole-containing compounds able to bind the FSS with high affinity and selectivity. Readily accessible synthetically, these compounds are less toxic than previously reported olefin congeners.
View Article and Find Full Text PDFAPOBEC3G (A3G) belongs to the AID/APOBEC protein family of cytidine deaminases (CDA) that bind to nucleic acids. A3G mutates the HIV genome by deamination of dC to dU, leading to accumulation of virus-inactivating mutations. Binding to cellular RNAs inhibits A3G binding to substrate single-stranded (ss) DNA and CDA activity.
View Article and Find Full Text PDFCamptothecin (CPT) is a natural product discovered to be active against various cancers through its ability to inhibit Topoisomerase I (TOP1). CPT analogs also have anti-HIV-1 (HIV) activity that was previously shown to be independent of TOP1 inhibition. We show that a cancer inactive CPT analog (O2-16) inhibits HIV infection by disrupting multimerization of the HIV protein Vif.
View Article and Find Full Text PDFThe APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like) family of proteins have diverse and important functions in human health and disease. These proteins have an intrinsic ability to bind to both RNA and single-stranded (ss) DNA. Both function and tissue-specific expression varies widely for each APOBEC protein.
View Article and Find Full Text PDFThere are eleven members in the human APOBEC family of proteins that are evolutionarily related through their zinc-dependent cytidine deaminase domains. The human APOBEC gene clusters arose on chromosome 6 and 22 through gene duplication and divergence to where current day APOBEC proteins are functionally diverse and broadly expressed in tissues. APOBEC serve enzymatic and non enzymatic functions in cells.
View Article and Find Full Text PDFHuman Immunodeficiency Virus (HIV) type 1 uses a -1 programmed ribosomal frameshift (-1 PRF) event to translate its enzymes from the same transcript used to encode the virus' structural proteins. The frequency of this event is highly regulated, and significant deviation from the normal 5-10% frequency has been demonstrated to decrease viral infectivity. Frameshifting is primarily regulated by the Frameshift Stimulatory Signal RNA (FSS-RNA), a thermodynamically stable, highly conserved stem loop that has been proposed as a therapeutic target.
View Article and Find Full Text PDFWiley Interdiscip Rev RNA
March 2015
Cytidine deaminases have important roles in the regulation of nucleoside/deoxynucleoside pools for DNA and RNA synthesis. The APOBEC family of cytidine deaminases (named after the first member of the family that was described, Apolipoprotein B mRNA Editing Catalytic Subunit 1, also known as APOBEC1 or A1) is a fascinating group of mutagenic proteins that use RNA and single-stranded DNA (ssDNA) as substrates for their cytidine or deoxycytidine deaminase activities. APOBEC proteins and base-modification nucleic acid editing have been the subject of numerous publications, reviews, and speculation.
View Article and Find Full Text PDFThe life cycle of the human immunodeficiency virus type 1 (HIV-1) has an absolute requirement for ribosomal frameshifting during protein translation in order to produce the polyprotein precursor of the viral enzymes. While an RNA stem-loop structure (the "HIV-1 Frameshift Stimulating Signal", or HIV-1 FSS) controls the frameshift efficiency and has been hypothesized as an attractive therapeutic target, developing compounds that selectively bind this RNA and interfere with HIV-1 replication has proven challenging. Building on our prior discovery of a "hit" molecule able to bind this stem-loop, we now report the development of compounds displaying high affinity for the HIV-1 FSS.
View Article and Find Full Text PDFAPOBEC1 is a cytidine deaminase that edits messenger RNAs and was the first enzyme in the APOBEC family to be functionally characterized. Under appropriate conditions APOBEC1 also deaminates deoxycytidine in single-stranded DNA (ssDNA). The other ten members of the APOBEC family have not been fully characterized however several have deoxycytidine deaminase activity on ssDNAs.
View Article and Find Full Text PDFHuman APOBEC3G (hA3G) is a cytidine deaminase active on HIV single-stranded DNA. Small angle x-ray scattering and molecular envelope restorations predicted a C-terminal dimeric model for RNA-depleted hA3G in solution. Each subunit was elongated, suggesting that individual domains of hA3G are solvent-exposed and therefore may interact with other macromolecules even as isolated substructures.
View Article and Find Full Text PDFHuman APOBEC3G (hA3G) is a host factor that defends against HIV-1 as well as other exogenous retroviruses and endogenous retroelements. To this end, hA3G is restricted to the cytoplasm of T lymphocytes where it interacts with viral RNA and proteins to assemble with viral particles causing a post-entry block during reverse transcription. hA3G also exhibits a mechanism to inhibit the reverse transcription of retroelements by RNA binding and sequestration into mRNA processing centers in the cytoplasm.
View Article and Find Full Text PDFHuman APOBEC3G (hA3G) is a cytidine deaminase that restricts human immunodeficiency virus (HIV)-1 infection in a vif (the virion infectivity factor from HIV)-dependent manner. hA3G from HIV-permissive activated CD4+ T-cells exists as an inactive, high molecular mass (HMM) complex that can be transformed in vitro into an active, low molecular mass (LMM) variant comparable with that of HIV-non-permissive CD4+ T-cells. Here we present low resolution structures of hA3G in HMM and LMM forms determined by small angle x-ray scattering and advanced shape reconstruction methods.
View Article and Find Full Text PDFBiochem Biophys Res Commun
November 2006
Human APOBEC3G (hA3G) is a member of the APOBEC-1 related protein (ARP) family of cytidine deaminases. hA3G functions as a natural defense against endogenous retrotransposons and a multitude of retroviruses, most notably human immunodeficiency virus type 1 (HIV-1). Nothing is known about the cellular function of hA3G, however, upon HIV-1 infection hA3G functions as an antiviral factor by mutating viral single-stranded DNA during reverse transcription.
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