Molecular strategies to inhibit HIV-1 replication

Nielsen, Mads; Pedersen, Finn Skou; Kjems, Jørgen

doi:10.1186/1742-4690-2-10

Cited by 62 publications

(15 citation statements)

References 84 publications

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“…The common characteristic between the above-described examples of antiviral activity from algal polysaccharide is the presence of sulfated groups in their chemical structure [96]. Although these compounds might act on Stage III of viral infection, selectively inhibiting reverse transcriptase in the case of HIV, thus hampering production of new viral particles after infection [97], the inhibitory effect generally might refer to Stage I of viral infection. This is a crucial aspect to investigate since the antiviral property starts with the interaction between the molecule and the positive charges of the virus or on the cell surface, preventing penetration of the former into the host cells [98].…”

Section: Marine Antioxidants and Antiviral Activitymentioning

confidence: 99%

Marine Algal Antioxidants as Potential Vectors for Controlling Viral Diseases

et al. 2020

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As the COVID-19 epidemic expands in the world, and with the previous SARS epidemic, avian flu, Ebola and AIDS serving as a warning, biomedical and biotechnological research has the task to find solutions to counteract viral entry and pathogenesis. A novel approach can come from marine chemodiversity, recognized as a relevant source for developing a future natural "antiviral pharmacy". Activities of antioxidants against viruses can be exploited to cope with human viral infection, from single individual infections to protection of populations. There is a potentially rich and fruitful reservoir of such compounds thanks to the plethora of bioactive molecules and families present in marine microorganisms. The aim of this communication is to present the state-of-play of what is known on the antiviral activities recognized in (micro)algae, highlighting the different molecules from various algae and their mechanisms of actions, when known. Given the ability of various algal molecules-mainly sulfated polysaccharides-to inhibit viral infection at Stage I (adsorption and invasion of cells), we envisage a need to further investigate the antiviral ability of algae, and their mechanisms of action. Given the advantages of microalgal production compared to other organisms, the opportunity might become reality in a short period of time.

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Section: Marine Antioxidants and Antiviral Activitymentioning

confidence: 99%

Marine Algal Antioxidants as Potential Vectors for Controlling Viral Diseases

et al. 2020

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“…To reduce viral infectivity, several molecular strategies have been developed to target intracellular HIV-1 proteins, including Env (13). By the exploitation of the Env-CD4 binding affinity occurring in the ER and by using anti-gp160 intracellular singlechain antibodies, interference with gp160 maturation and trafficking was successfully obtained (14)(15)(16)(17)(18)(19)(20)(21).…”

mentioning

confidence: 99%

Reduction of HIV-1 Infectivity through Endoplasmic Reticulum-Associated Degradation-Mediated Env Depletion

Casini

Olivieri

Vecchi

et al. 2015

J Virol

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During the HIV-1 replicative cycle, the gp160 envelope is processed in the secretory pathway to mature into the gp41 and gp120 subunits. Misfolded proteins located within the endoplasmic reticulum (ER) are proteasomally degraded through the ER-associated degradation (ERAD) pathway, a quality control system operating in this compartment. Here, we exploited the ERAD pathway to induce the degradation of gp160 during viral production, thus leading to the release of gp120-depleted viral particles.T he precursor of the viral envelope, gp160, undergoes extensive posttranslational modification in the endoplasmic reticulum (ER) and is subsequently cleaved into two subunits, gp120 and gp41, within the Golgi apparatus. The processed Env subunits then reach the plasma membrane, where they are incorporated into the budding viral particles (1).Here, we present a novel strategy to reduce HIV-1 infectivity through the depletion of gp120 from viral particles. This approach is based on gp160 degradation during viral production obtained by using the targeted ER-associated degradation (TED) approach. This recently developed technique exploits the ER-associated degradation pathway (ERAD) machinery to promote specific downregulation of target proteins trafficking through the secretory pathway (2). TED uses chimeric molecules termed "degradins" that are characterized by two functional moieties: a target recognition moiety and a degradation-inducing moiety composed of the C-terminal fragment (amino acids [aa] 402 to 773) of the cellular ER-resident protein SEL1L. This protein is involved in the ERAD pathway by selecting misfolded proteins for retrotranslocation from the ER lumen to the cytosol for proteasomal degradation (3). SEL1L chimeras designed against selected targets have been demonstrated to specifically force the interaction of the target protein with the retrotranslocation machinery, leading to the export of the protein from the ER and its subsequent degradation in the cytosol (2).To obtain gp160-specific degradins, we prepared SEL1L chimeras containing different target recognition moieties directed against various epitopes of HIV-1 gp160. We used three singlechain antibody fragments (scFv) derived from monoclonal antibodies (MAbs): Chessie1339, obtained from the anti-gp160 hybridoma Chessie 13-39.1 (4), to produce the 1339-SEL1L degradin; and VRC01 and VRC03, derived from two broad neutralizing MAbs directed toward the CD4 binding site of gp120 (5), to produce the VRC01-SEL1L and VRC03-SEL1L degradins, respectively. A general scheme of degradin design is reported in Fig. 1A.We next tested the efficacy of the anti-gp160 degradins in 293T cells coexpressing the SEL-1L chimeras with a codon-optimized gp160. In these experiments, gp160 is expressed from a construct containing the codon-optimized sequence for gp120 (isolate JRFL, clade B) from the pSyngp120 plasmid (6) in frame with the optimized sequence for gp41 derived by gene synthesis from the same isolate. In addition, the N terminus of gp160 was modified by substituting t...

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“…Gene therapy trials, mainly applied trans-cleaving hairpin ribozymes and hammerhead ribozymes directed against HIV-1 [83]. Gene therapy trials, mainly applied trans-cleaving hairpin ribozymes and hammerhead ribozymes directed against HIV-1 [83].…”

Section: Trans-cleaving Ribozymesmentioning

confidence: 99%

Drugs Made of RNA: Development and Application of Engineered RNAs for Gene Therapy

Drude¹,

Dombos²,

Vauléon

et al. 2007

MRMC

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During the past decade, RNA has become a focus of investigation into new therapeutic schemes: antisense RNA, interfering RNA and trans-cleaving ribozymes are used to silence undesired gene expression. As an additional option with its own therapeutic potential, ribozymes may be employed to specifically alter the sequence of RNA. Among these RNA based strategies the mode of action varies: while antisense and interfering RNAs are capable of making specific contacts to other RNA molecules with the result of employing the cellular machinery for degradation of the RNA target, trans-cleaving ribozymes fold into specific three-dimensional structures to form catalytic centres and to specifically cleave a chosen RNA target. Beyond this, trans-splicing ribozymes have been engineered to first cleave a RNA target followed by ligation of a new RNA fragment delivered with the ribozyme. The latter strategy potentially extends the application of ribozymes from inhibition of gene expression to RNA repair, i. e. correction of genetic disorders at the level of RNA, and has already shown promising results in cell culture experiments. On the other side, advances in RNA synthesis, ribozyme engineering, delivery methods and expression systems have greatly enhanced the prospects of ribozymes, antisense and interfering RNAs in gene therapy. This review provides an overview of existing strategies for potential RNA based gene therapy. It is focussed on the engineering of ribozymes and functional RNAs to be used as drugs and on the basic molecular principles of their action.

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Molecular strategies to inhibit HIV-1 replication

Cited by 62 publications

References 84 publications

Marine Algal Antioxidants as Potential Vectors for Controlling Viral Diseases

Marine Algal Antioxidants as Potential Vectors for Controlling Viral Diseases

Reduction of HIV-1 Infectivity through Endoplasmic Reticulum-Associated Degradation-Mediated Env Depletion

Drugs Made of RNA: Development and Application of Engineered RNAs for Gene Therapy

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