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  • 1
    Language: English
    In: Science (New York, N.Y.), 16 March 2012, Vol.335(6074), pp.1313-4
    Description: New insights into the complex interplay between human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) and their primate hosts are being gleaned from studies of viral accessory proteins. It is now apparent that these proteins (which are often dispensable for replication in cell culture) frequently antagonize host innate and adaptive immune responses. In several cases, accessory proteins repress specific host cell inhibitors of infection known as restriction factors ( 1 ). That the genes encoding restriction factors have been subjected to Darwinian selection pressure suggests the evolutionary importance of their function ( 2 , 3 ). These general themes have recently been reprised through studies on the Vpx accessory protein of HIV-2/SIVsmm and the discovery of its host cell target called sterile alpha motif (SAM) and histidine/aspartic acid (HD) domain–containing protein 1 (SAMHD1).
    Keywords: HIV Infections -- Virology ; HIV-1 -- Immunology ; Monomeric Gtp-Binding Proteins -- Metabolism ; Myeloid Cells -- Virology
    ISSN: 00368075
    E-ISSN: 1095-9203
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  • 2
    In: Nature, 2013, Vol.502(7472), p.559
    Description: Animal cells harbour multiple innate effector mechanisms that inhibit virus replication. For the pathogenic retrovirus human immunodeficiency virus type 1 (HIV-1), these include widely expressed restriction factors^sup 1^, such as APOBEC3 proteins^sup 2^, TRIM5-α^sup 3^, BST2 (refs 4, 5) and SAMHD1 (refs 6, 7), as well as additional factors that are stimulated by type 1 interferon (IFN)^sup 8-14^. Here we use both ectopic expression and gene-silencing experiments to define the human dynamin-like, IFN-induced myxovirus resistance 2 (MX2, also known as MXB) protein as a potent inhibitor of HIV-1 infection and as a key effector of IFN-α-mediated resistance to HIV-1 infection. MX2 suppresses infection by all HIV-1 strains tested, has equivalent or reduced effects on divergent simian immunodeficiency viruses, and does not inhibit other retroviruses such as murine leukaemia virus. The Capsid region of the viral Gag protein dictates susceptibility to MX2, and the block to infection occurs at a late post-entry step, with both the nuclear accumulation and chromosomal integration of nascent viral complementary DNA suppressed. Finally, human MX1 (also known as MXA), a closely related protein that has long been recognized as a broadly acting inhibitor of RNA and DNA viruses, including the orthomyxovirus influenza A virus^sup 15,16^, does not affect HIV-1, whereas MX2 is ineffective against influenza virus. MX2 is therefore a cell-autonomous, anti-HIV-1 resistance factorwhose purposeful mobilization may represent a new therapeutic approach for the treatment of HIV/AIDS. [PUBLICATION ]
    Keywords: Cell Line–Genetics ; Cell Nucleus–Virology ; Cell Nucleus–Immunology ; Cells, Cultured–Metabolism ; HIV Infections–Prevention & Control ; HIV Infections–Virology ; HIV Infections–Classification ; HIV Infections–Enzymology ; HIV-1–Genetics ; HIV-1–Physiology ; HIV-1–Immunology ; HIV-1–Deficiency ; Humans–Genetics ; Interferons–Metabolism ; Myxovirus Resistance Proteins–Biosynthesis ; Myxovirus Resistance Proteins–Genetics ; Myxovirus Resistance Proteins–Metabolism ; RNA, Viral–Genetics ; RNA, Viral–Genetics ; RNA, Viral–Genetics ; Reverse Transcription–Genetics ; Species Specificity–Genetics ; Substrate Specificity–Genetics ; Virus Integration–Genetics ; Virus Replication–Genetics ; Rodents ; Microbiology ; Proteins ; Viruses ; Infections ; Influenza ; Lymphocytes ; Gene Expression ; Mx2 Protein, Human ; Myxovirus Resistance Proteins ; RNA, Viral ; Interferons;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    Language: English
    In: Chemistry – A European Journal, 01 September 2014, Vol.20(36), pp.11479-11487
    Description: Rational design in combination with a screening process was used to develop affinity polymers for a specific binding site on the surface of immunoglobulin G (IgG) proteins. The concept starts with the identification of critical amino acid residues on the protein interface and their topological arrangement. Appropriate binding monomers were subsequently synthesized. Together with a sugar monomer (2–5 equiv) for water solubility and a dansyl monomer (0.5 equiv) as a fluorescent label, they were subjected in aqueous solution to linear radical copolymerization in various compositions (e.g., azobisisobutyronitrile (AIBN), homogeneous water/DMF mixtures). After ultrafiltration and lyophilization, colorless dry water‐soluble powders were obtained. NMR spectroscopic and gel permeation chromatography (GPC) characterization indicated molecular weights between 30 and 500 kD and confirmed retention of monomer composition as well as the absence of monomers. In a competitive enzyme‐linked immunosorbent assay (ELISA) screen of the polymer libraries (20–50 members), few copolymers qualified as strong and selective binders for the protein A binding site on the Fc fragment of the antibody. Their monomer composition precisely reflected the critical amino acids found at the interface. The simple combination of a charged and a nonpolar binding monomer sufficed for selective submicromolar IgG recognition by the synthetic polymer. Affinities were confirmed by fluorescence titrations; they increased with decreasing salt load but remained largely unaltered at lowered pH. Other proteins, including those of similar size and isoelectric point (pI), were bound 10–1000 times less tightly. This example indicates that interaction domains in other proteins may also be targeted by synthetic polymers if their comonomer composition reflects the nature and arrangement of amino acid residues on the protein surface. : Designed affinity polymers recognize the hot spot on a protein surface by virtue of their carefully selected binding monomers. Here, it is the protein A binding site on the Fc fragment of immunoglobulin G proteins (see figure), which is essential for medicinal antibody purification.
    Keywords: Antibodies ; Immunoglobulins ; Polymers ; Protein Recognition ; Supramolecular Chemistry
    ISSN: 0947-6539
    E-ISSN: 1521-3765
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  • 4
    Language: English
    In: Chemistry - A European Journal, 08/06/2018, Vol.24(44), pp.11235-11235
    ISSN: Chemistry - A European Journal
    E-ISSN: 09476539
    Source: Wiley (via CrossRef)
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  • 5
    Language: English
    In: Chemistry – A European Journal, 06 August 2018, Vol.24(44), pp.11332-11343
    Description: A new synthetic access to molecular tweezers with one or two aliphatic phosphate ester groups in the central benzene spacer‐unit is presented. Alkynyl ester groups offer the prospect to attach additional functional units by click chemistry and greatly broaden the scope of these tools for chemical biology. We present two alternative strategies: the trichloroacetonitrile method involves activation of only one OH group of each phosphoric acid substituent by way of trichloroacetimidate intermediates and subsequent introduction of an aliphatic ester alcohol moiety. The method is versatile, robust and combines simple workup with high yields. Mono‐ and disubstituted novel host structures are thus accessible in a convenient way. Alternatively, the phosphoramidite strategy activates the hydroquinone precursor by way of phosphoramidite intermediates and couples the desired ester alcohols followed by mild oxidation to the desired phosphate esters. Each step of the synthesis is carried out at very mild conditions and allows to combine sensitive host candidates and recognition elements. After neutralization of the phosphoric acids to water‐soluble tri‐ and tetra‐anions the cavities of the new tweezer derivatives are open to bind lysine and arginine as well as peptidic guests. The concept of introducing clickable alkynyl phosphates to free OH groups may be transferred to other major macrocyclic host classes to introduce additional recognition elements, biomolecules or fluorescence labels. chemistry can be exploited to conveniently attach additional functional elements to molecular tweezers with free OH groups.
    Keywords: Alkynols ; Amino Acids ; Esters ; Molecular Tweezers ; Peptides
    ISSN: 0947-6539
    E-ISSN: 1521-3765
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  • 6
    In: European Journal of Organic Chemistry, 26 April 2017, Vol.2017(16), pp.2223-2229
    Description: The inhibition of PARP‐1 (poly[ADP‐ribose]polymerase 1), a key enzyme for DNA quality control, has been achieved with synthetic molecular tweezers through a noncompetitive mechanism with an IC value of 3 µ. Displacement as well as electrophoretic mobility shift assays and molecular dynamics experiments point to a simultaneous inclusion of lysine side‐chains in the cavity of the tweezers and the coordination of one phosphate arm to the central Zn ion of the zinc finger; thereby, lesioned DNA is displaced. A molecular‐dynamics (MD) simulation of the putative complex between zinc finger FII (PARP‐1, poly[ADP‐ribose]polymerase 1) and a molecular tweezers ligand reveals a new noncompetitive inhibition mechanism with reference to the substrate: note the simultaneous inclusion of Lys‐70 inside the tweezers cavity with coordination at the Zn ion.
    Keywords: Enzymes ; Enzyme Inhibition ; Molecular Clips ; Molecular Tweezers ; Host–Guest Systems ; Molecular Dynamics
    ISSN: 1434-193X
    E-ISSN: 1099-0690
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  • 7
    Language: English
    In: Current HIV Research, 2016, Vol.14(3), p.183-210
    Description: Background: Human immunodeficiency virus 1 (HIV-1) infection is the primary cause of the acquired immunodeficiency syndrome (AIDS). Worldwide, approximately 37 million people are infected (UNAIDS, 2014), most of them in developing countries. A vaccine is not available and current treatment strategies and diagnostics are expensive and require appropriate medical infrastructure. As a lentivirus of the family Retroviridae, HIV-1 reverse transcribes its RNA into double stranded DNA that integrates into the host genome during infection, establishing a stably integrated provirus that serves as a template for the production of progeny virus. The earliest steps during infection are critical for onset of disease, progression and clinical outcome. Methods: Here we review the current literature of known interactions between host cell factors and HIV-1 in the early infection steps and discuss them as possible targets for new treatment strategies. Results: Targeting the earliest interactions of the virus with host cell factors is an attractive way to prevent provirus formation, underlined by the evolution of multiple antiviral host cell barriers at this stage. HIV-1 has to overcome these restrictions by either counteracting them directly or by escape mutations. At the same time, viral fitness requires preservation of viral structures that interact with host components, thereby avoiding recognition of viral nucleic acids, like reverse transcription intermediates, by innate pattern recognition receptors. Conclusion: Future drug development, improvement of existing drugs acting in the earliest stages of the HIV-1 replication cycle as well as specifically targeting interactions of viral components with host cell factors required for HIV-1 infection will likely advance current therapy strategies.
    Keywords: Hiv-1 Interferon-Stimulated Genes Uncoating Host Dependency Factors Host Restriction/Resistance Factors Capsid Entry Early Life Cycle.
    ISSN: 1570-162X
    E-ISSN: 1873-4251
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  • 8
    Language: English
    In: The Journal of Virology, 2010, Vol. 84(23), p.12463
    Description: TRIM5 alpha proteins recruit and restrict incoming cytoplasmic retroviruses. Primate TRIM5 alpha sequence diversity underlies species-specific restriction and is likely caused by selective pressure from ancient pathogenic infections. Here we show that TRIM5 alpha from the European brown hare restricts diverse retroviruses. Furthermore, it differs significantly in sequence from TRIM5 alpha from the closely related rabbit, suggesting evolutionary changes in the last 12 million years since these species diverged. We propose that, like primates, lagomorphs have been subject to selective pressure from TRIM5-sensitive viruses, possibly related to the endogenous lentivirus RELIK found in both rabbits and hares.
    Keywords: Biology;
    ISSN: 0022-538X
    ISSN: 0022538X
    E-ISSN: 10985514
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  • 9
    Language: English
    In: Biomacromolecules, 12 June 2017, Vol.18(6), pp.1772-1784
    Description: This account presents a general method for the construction of polymeric surface binders for digestion enzymes. Two prominent parts, namely, the modification of the copolymer composition and the screening assay for the most powerful inhibitors are both amenable to parallelization. The concept hinges on the appropriate selection of amino-acid-selective comonomers, their free radical copolymerization, and subsequent screening of the resulting copolymer library for efficient enzyme inhibition. A microscale synthetic procedure for the copolymerization process was developed, which produces water-soluble affinity polymers that can be stored for years at room temperature. Initial parallel screening was conducted in standard enzyme assays to identify polymeric inhibitors, which were subsequently subjected to determination of IC values for their target enzyme. For all digestion enzymes, except elastase, a number of polymer inhibitors were found, some of which were selective toward one or two protein targets. Since the key monomers of the best inhibitors bind to amino acid residues in the direct vicinity of the active site, we conclude that efficient coverage of the immediate environment by the copolymers is critical. Strong interference with enzymatic activity is brought about by blocking the substrate access and product exit to and from the active site.
    Keywords: Benzamidines -- Chemistry ; Diphosphonates -- Chemistry ; Enzyme Inhibitors -- Chemistry ; Pancreatic Elastase -- Chemistry ; Polymers -- Chemistry ; Serine Proteases -- Chemistry
    ISSN: 15257797
    E-ISSN: 1526-4602
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  • 10
    In: EMBO Journal, 04 August 2015, Vol.34(15), pp.2078-2095
    Description: 5α is an antiviral, cytoplasmic, E3 ubiquitin (Ub) ligase that assembles on incoming retroviral capsids and induces their premature dissociation. It inhibits reverse transcription of the viral genome and can also synthesize unanchored polyubiquitin (polyUb) chains to stimulate innate immune responses. Here, we show that 5α employs the E2 Ub‐conjugating enzyme Ube2W to anchor the Lys63‐linked polyUb chains in a process of 5α auto‐ubiquitination. Chain anchoring is initiated, in cells and , through Ube2W‐catalyzed monoubiquitination of 5α. This modification serves as a substrate for the elongation of anchored Lys63‐linked polyUb chains, catalyzed by the heterodimeric E2 enzyme Ube2N/Ube2V2. Ube2W targets multiple 5α internal lysines with Ub especially lysines 45 and 50, rather than modifying the N‐terminal amino group, which is instead αN‐acetylated in cells. E2 depletion or Ub mutation inhibits 5α ubiquitination in cells and restores restricted viral reverse transcription, but not infection. Our data indicate that the stepwise formation of anchored Lys63‐linked polyUb is a critical early step in the 5α restriction mechanism and identify the E2 Ub‐conjugating cofactors involved. The anti‐retroviral factor 5α restricts viral reverse transcription by recruiting two E2 Ub conjugation enzymes, leading to K63‐polyubiquitin chain anchoring to multiple internal 5α lysine residues. Ube2W, the heterodimer Ube2N/Ube2V2, and ubiquitin lysine 63 are each required for restriction of retroviral reverse transcription by TRIM5α. The TRIM5α‐mediated blocks to retroviral reverse transcription and infection can be genetically uncoupled. Ube2W serves to anchor Ube2N/V2‐synthesised K63‐linked polyubiquitin to several internal lysine residues in TRIM5α in vitro, principally RING lysines 45 and 50. In cells, the N‐terminus of TRIM5α is quantitatively demethionylated and αN‐acetylated, preventing N‐terminal ubiquitin conjugation by Ube2W. The anti‐retroviral factor 5α restricts viral reverse transcription by recruiting two E2 Ub conjugation enzymes, leading to K63‐polyubiquitin chain anchoring to multiple internal 5α lysine residues.
    Keywords: Restriction ; Trim 5α ; Ube2n ; Ube2w ; Ubiquitin
    ISSN: 0261-4189
    E-ISSN: 1460-2075
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