Imperial College London
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Professor Peter Cherepanov

Faculty of Medicine, Department of Infectious Disease

Professor of Molecular Virology
 
 
 
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p.cherepanov

 
 
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Location

 

Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
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137 results found

Hare S, Engelman A, Cherepanov P, 2011, HIV-1 Integrase: Mechanism and Inhibitor Design, HIV-1 Integrase, Editors: Neamati, Publisher: Wiley, ISBN: 9780470184745

This book comprehensively covers the mechanisms of action and inhibitor design for HIV-1 integrase. It serves as a resource for scientists facing challenging drug design issues and researchers in antiviral drug discovery.

Book chapter

Cherepanov P, Maertens GN, Hare S, 2011, Structural insights into the retroviral DNA integration apparatus, CURRENT OPINION IN STRUCTURAL BIOLOGY, Vol: 21, Pages: 249-256, ISSN: 0959-440X

Journal article

Li X, Krishnan L, Cherepanov P, Engelman Aet al., 2011, Structural biology of retroviral DNA integration, VIROLOGY, Vol: 411, Pages: 194-205, ISSN: 0042-6822

Journal article

Hare S, Vos AM, Clayton RF, Thuring JW, Cummings MD, Cherepanov Pet al., 2010, Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 107, Pages: 20057-20062, ISSN: 0027-8424

Journal article

Maertens GN, Hare S, Cherepanov P, 2010, The mechanism of retroviral integration from X-ray structures of its key intermediates, Nature, Vol: 468, Pages: 326-U217, ISSN: 0028-0836

To establish productive infection, a retrovirus must insert a DNA replica of its genome into host cell chromosomal DNA1,2. This process is operated by the intasome, a nucleoprotein complex composed of an integrase tetramer (IN) assembled on the viral DNA ends3,4. The intasome engages chromosomal DNA within a target capture complex to carry out strand transfer, irreversibly joining the viral and cellular DNA molecules. Although several intasome/transpososome structures from the DDE(D) recombinase superfamily have been reported4,5,6, the mechanics of target DNA capture and strand transfer by these enzymes remained unclear. Here we report crystal structures of the intasome from prototype foamy virus in complex with target DNA, elucidating the pre-integration target DNA capture and post-catalytic strand transfer intermediates of the retroviral integration process. The cleft between IN dimers within the intasome accommodates chromosomal DNA in a severely bent conformation, allowing widely spaced IN active sites to access the scissile phosphodiester bonds. Our results resolve the structural basis for retroviral DNA integration and provide a framework for the design of INs with altered target sequences.

Journal article

Krishnan L, Li X, Naraharisetty HL, Hare S, Cherepanov P, Engelman Aet al., 2010, Structure-based modeling of the functional HIV-1 intasome and its inhibition, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 107, Pages: 15910-15915, ISSN: 0027-8424

Journal article

Cherepanov P, 2010, Integrase illuminated, EMBO REPORTS, Vol: 11, Pages: 328-328, ISSN: 1469-221X

Journal article

Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov Pet al., 2010, Retroviral intasome assembly and inhibition of DNA strand transfer, Nature, Vol: 464, Pages: 232-236, ISSN: 0028-0836

Integrase is an essential retroviral enzyme that binds both termini of linear viral DNA and inserts them into a host cell chromosome. The structure of full-length retroviral integrase, either separately or in complex with DNA, has been lacking. Furthermore, although clinically useful inhibitors of HIV integrase have been developed, their mechanism of action remains speculative. Here we present a crystal structure of full-length integrase from the prototype foamy virus in complex with its cognate DNA. The structure shows the organization of the retroviral intasome comprising an integrase tetramer tightly associated with a pair of viral DNA ends. All three canonical integrase structural domains are involved in extensive protein–DNA and protein–protein interactions. The binding of strand-transfer inhibitors displaces the reactive viral DNA end from the active site, disarming the viral nucleoprotein complex. Our findings define the structural basis of retroviral DNA integration, and will allow modelling of the HIV-1 intasome to aid in the development of antiretroviral drugs.

Journal article

Hughes S, Jenkins V, Dar MJ, Engelman A, Cherepanov Pet al., 2010, Transcriptional Co-activator LEDGF Interacts with Cdc7-Activator of S-phase Kinase (ASK) and Stimulates Its Enzymatic Activity, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 285, Pages: 541-554

Journal article

Hare S, Cherepanov P, Wang J, 2009, Application of general formulas for the correction of a lattice-translocation defect in crystals of a lentiviral integrase in complex with LEDGF, ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, Vol: 65, Pages: 966-973, ISSN: 2059-7983

Journal article

Hare S, Di Nunzio F, Labeja A, Wang J, Engelman A, Cherepanov Pet al., 2009, Structural Basis for Functional Tetramerization of Lentiviral Integrase, PLOS PATHOGENS, Vol: 5, ISSN: 1553-7366

Journal article

Cherepanov P, Debyser Z, De Clercq E, 2009, Integrase cofactor, US7514233

Patent

Yan N, Cherepanov P, Daigle JE, Engelman A, Lieberman Jet al., 2009, The SET Complex Acts as a Barrier to Autointegration of HIV-1, PLOS PATHOGENS, Vol: 5, ISSN: 1553-7366

Journal article

Zaitseva L, Cherepanov P, Leyens L, Wilson SJ, Rasaiyaah J, Fassati Aet al., 2009, HIV-1 exploits importin 7 to maximize nuclear import of its DNA genome, RETROVIROLOGY, Vol: 6

Journal article

Hare S, Shun M-C, Gupta SS, Valkov E, Engelman A, Cherepanov Pet al., 2009, A Novel Co-Crystal Structure Affords the Design of Gain-of-Function Lentiviral Integrase Mutants in the Presence of Modified PSIP1/LEDGF/p75, PLOS PATHOGENS, Vol: 5, ISSN: 1553-7366

Journal article

Valkov E, Gupta SS, Hare S, Helander A, Roversi P, McClure M, Cherepanov Pet al., 2009, Functional and structural characterization of the integrase from the prototype foamy virus, NUCLEIC ACIDS RESEARCH, Vol: 37, Pages: 243-255, ISSN: 0305-1048

Journal article

Hare S, Cherepanov P, 2009, The Interaction Between Lentiviral Integrase and LEDGF: Structural and Functional Insights, Viruses, Vol: 1, Pages: 780-801

Journal article

Engelman A, Cherepanov P, 2008, The lentiviral integrase binding protein LEDGF/p75 and HIV-1 replication, PLOS PATHOGENS, Vol: 4, ISSN: 1553-7366

Journal article

Shun M-C, Raghavendra NK, Vandegraaff N, Daigle JE, Hughes S, Kellam P, Cherepanov P, Engelman Aet al., 2007, LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration, GENES & DEVELOPMENT, Vol: 21, Pages: 1767-1778, ISSN: 0890-9369

Journal article

Rahman S, Lu R, Vandegraaff N, Cherepanov P, Engelman Aet al., 2007, Structure-based mutagenesis of the integrase-LEDGF/p75 interface uncouples a strict correlation between in vitro protein binding and HIV-1 fitness, VIROLOGY, Vol: 357, Pages: 79-90, ISSN: 0042-6822

Journal article

Cherepanov P, 2007, LEDGF/p75 interacts with divergent lentiviral integrases and modulates their enzymatic activity in vitro, Nucleic Acids Research, Vol: 35, Pages: 113-124, ISSN: 0305-1048

Transcriptional co-activator LEDGF/p75 is the major cellular interactor of HIV-1 integrase (IN), critical to efficient viral replication. In this work, a series of INs from the Betaretrovirus, Gammaretrovirus, Deltaretrovirus, Spumavirus and Lentivirus retroviral genera were tested for interaction with the host factor. None of the non-lentiviral INs possessed detectable affinity for LEDGF in either pull-down or yeast two-hybrid assays. In contrast, all lentiviral INs examined, including those from bovine immunodeficiency virus (BIV), maedi-visna virus (MVV) and equine infectious anemia virus (EIAV) readily interacted with LEDGF. Mutation of Asp-366 to Asn in LEDGF ablated the interaction, suggesting a common mechanism of the host factor recognition by the INs. LEDGF potently stimulated strand transfer activity of divergent lentiviral INs in vitro . Unprecedentedly, in the presence of the host factor, EIAV IN almost exclusively catalyzed concerted integration, whereas HIV-1 IN promoted predominantly half-site integration, and BIV IN was equally active in both types of strand transfer. Concerted BIV and EIAV integration resulted in 5 bp duplications of the target DNA sequences. These results confirm that the interaction with LEDGF is conserved within and limited to Lentivirus and strongly argue that the host factor is intimately involved in the catalysis of lentiviral DNA integration.

Journal article

Maertens GN, Cherepanov P, Engelman A, 2006, Transcriptional co-activator p75 binds and tethers the Myc-interacting protein JPO2 to chromatin, JOURNAL OF CELL SCIENCE, Vol: 119, Pages: 2563-2571, ISSN: 0021-9533

Journal article

Turlure F, Maertens G, Rahman S, Cherepanov P, Engelman Aet al., 2006, A tripartite DNA-binding element, comprised of the nuclear localization signal and two AT-hook motifs, mediates the association of LEDGF/p75 with chromatin in vivo, Nucleic Acids Research, Vol: 34, Pages: 1653-1665, ISSN: 1362-4962

Lens epithelium-derived growth factor p75 (LEDGF/p75) is a DNA-binding, transcriptional co-activator that participates in HIV-1 integration site targeting. Using complementary approaches, we determined the mechanisms of LEDGF/p75 DNA-binding in vitro and chromatin-association in living cells. The binding of highly-purified, recombinant protein was assayed by surface plasmon resonance (SPR) and electrophoretic mobility gel shift. Neither assay revealed evidence for sequence-specific DNA-binding. Residues 146–197 spanning the nuclear localization signal (NLS) and two AT-hook motifs mediated non-specific DNA-binding, and DNA-binding deficient mutants retained the ability to efficiently stimulate HIV-1 integrase activity in vitro. Chromatin-association was assessed by visualizing the localization of EGFP fusion proteins in interphase and mitotic cells. Although a conserved N-terminal PWWP domain was not required for binding to condensed mitotic chromosomes, its deletion subtly affected the nucleoplasmic distribution of the protein during interphase. A dual AT-hook mutant associated normally with chromatin, yet when the mutations were combined with NLS changes or deletion of the PWWP domain, chromatin-binding function was lost. As the PWWP domain did not readily bind free DNA in vitro, our results indicate that chromatin-association is primarily affected through DNA-binding, with the PWWP domain likely contributing a protein interaction to the overall affinity of LEDGF/p75 for human chromatin.

Journal article

Engelman A, Cherepanov P, 2006, Recent advances in retroviral replication: Cellular machines and novel anti-viral defense mechanisms., Recent Advances in RNA Virus Replication, Editors: Hefferon, Kerala, India, Publisher: Transworld Research Network, Pages: 91-129, ISBN: 9788178952147

Book chapter

Cherepanov P, Ambrosio ALB, Rahman S, Ellenberger T, Engelman Aet al., 2005, Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 102, Pages: 17308-17313, ISSN: 0027-8424

Journal article

Lu R, Vandegraaff N, Cherepanov P, Engelman Aet al., 2005, Lys-34, dispensable for integrase catalysis, is required for preintegration complex function and human immunodeficiency virus type 1 replication, JOURNAL OF VIROLOGY, Vol: 79, Pages: 12584-12591, ISSN: 0022-538X

Journal article

Cherepanov P, Sun ZYJ, Rahman S, Maertens G, Wagner G, Engelman Aet al., 2005, Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75, NATURE STRUCTURAL & MOLECULAR BIOLOGY, Vol: 12, Pages: 526-532, ISSN: 1545-9993

Journal article

Hantson A, Fikkert V, Van Remoortel B, Pannecouque C, Cherepanov P, Matthews B, Holan G, De Clercq E, Vandamme A-M, Debyser Z, Witvrouw Met al., 2005, Mutations in both env and gag genes are required for HIV-1 resistance to the polysulfonic dendrimer SPL2923, as corroborated by chimeric virus technology., Antivir Chem Chemother, Vol: 16, Pages: 253-266, ISSN: 0956-3202

A drug-resistant NL4.3/SPL2923 strain has previously been generated by in vitro selection of HIV-1(NL4.3) in the presence of the polysulfonic dendrimer SPL2923 and mutations were reported in its gp120 gene (Witvrouw et al., 2000). Here, we further analysed the (cross) resistance profile of NL4.3/SPL2923. NL4.3/SPL2923 was found to contain additional mutations in gp41 and showed reduced susceptibility to SPL2923, dextran sulfate (DS) and enfuvirtide. To delineate to what extent the mutations in each env gene were accountable for the phenotypic (cross) resistance of NL4.3/SPL2923, the gp120-, gp41- and gp160-sequences derived from this strain were placed into a wild-type background using env chimeric virus technology (CVT). The cross resistance of NL4.3/SPL2923 towards DS was fully reproduced following gp160-recombination, while it was only partially reproduced following gp120- or gp41-recombination. The mutations in gp41 of NL4.3/SPL2923 were sufficient to reproduce the cross resistance to enfuvirtide. Unexpectedly, the reduced sensitivity towards SPL2923 was not fully reproduced after gp160-recombination. The search for mutations in NL4.3/SPL2923 in viral genes other than env revealed several mutations in the gene encoding the HIV p17 matrix protein (MA) and one mutation in the gene encoding the p24 capsid protein (CA). In order to analyse the impact of the gag mutations alone and in combination with the mutations in env on the phenotypic resistance towards SPL2923, we developed a novel p17- and p17/gp160-CVT. Phenotypic analysis of the NL4.3/SPL2923 p17- and p17/gp160-recombined strains indicated that the mutations in both env and gag have to be present to fully reproduce the resistance of NL4.3/SPL2923 towards SPL2923.

Journal article

Lu R, Limón A, Devroe E, Silver PA, Cherepanov P, Engelman Aet al., 2004, Class II integrase mutants with changes in putative nuclear localization signals are primarily blocked at a postnuclear entry step of human immunodeficiency virus type 1 replication, JOURNAL OF VIROLOGY, Vol: 78, Pages: 12735-12746, ISSN: 0022-538X

Journal article

Cherepanov P, Devroe E, Silver PA, Engelman Aet al., 2004, Identification of an evolutionarily conserved domain in human lens epithelium-derived growth factor/transcriptional co-activator p75 (LEDGF/p75) that binds HIV-1 integrase, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 279, Pages: 48883-48892, ISSN: 0021-9258

Journal article

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