Imperial College London

Professor Peter Cherepanov

Faculty of MedicineDepartment of Infectious Disease

Professor of Molecular Virology
 
 
 
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p.cherepanov

 
 
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Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
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131 results found

Baggen J, Jacquemyn M, Persoons L, Vanstreels E, Pye VE, Wrobel AG, Calvaresi V, Martin SR, Roustan C, Cronin NB, Reading E, Thibaut HJ, Vercruysse T, Maes P, De Smet F, Yee A, Nivitchanyong T, Roell M, Franco-Hernandez N, Rhinn H, Mamchak AA, Ah Young-Chapon M, Brown E, Cherepanov P, Daelemans Det al., 2023, TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry., Cell, Vol: 186, Pages: 3427-3442.e22

SARS-CoV-2 is associated with broad tissue tropism, a characteristic often determined by the availability of entry receptors on host cells. Here, we show that TMEM106B, a lysosomal transmembrane protein, can serve as an alternative receptor for SARS-CoV-2 entry into angiotensin-converting enzyme 2 (ACE2)-negative cells. Spike substitution E484D increased TMEM106B binding, thereby enhancing TMEM106B-mediated entry. TMEM106B-specific monoclonal antibodies blocked SARS-CoV-2 infection, demonstrating a role of TMEM106B in viral entry. Using X-ray crystallography, cryogenic electron microscopy (cryo-EM), and hydrogen-deuterium exchange mass spectrometry (HDX-MS), we show that the luminal domain (LD) of TMEM106B engages the receptor-binding motif of SARS-CoV-2 spike. Finally, we show that TMEM106B promotes spike-mediated syncytium formation, suggesting a role of TMEM106B in viral fusion. Together, our findings identify an ACE2-independent SARS-CoV-2 infection mechanism that involves cooperative interactions with the receptors heparan sulfate and TMEM106B.

Journal article

Freeman SL, Oliveira ASF, Gallio AE, Rosa A, Simitakou MK, Arthur CJ, Mulholland AJ, Cherepanov P, Raven ELet al., 2023, Heme binding to the SARS-CoV-2 spike glycoprotein., J Biol Chem, Vol: 299

The target for humoral immunity, SARS-CoV-2 spike glycoprotein, has become the focus of vaccine research and development. Previous work demonstrated that the N-terminal domain (NTD) of SARS-CoV-2 spike binds biliverdin-a product of heme catabolism-causing a strong allosteric effect on the activity of a subset of neutralizing antibodies. Herein, we show that the spike glycoprotein is also able to bind heme (KD = 0.5 ± 0.2 μM). Molecular modeling indicated that the heme group fits well within the same pocket on the SARS-CoV-2 spike NTD. Lined by aromatic and hydrophobic residues (W104, V126, I129, F192, F194, I203, and L226), the pocket provides a suitable environment to stabilize the hydrophobic heme. Mutagenesis of N121 has a substantive effect on heme binding (KD = 3000 ± 220 μM), confirming the pocket as a major heme binding location of the viral glycoprotein. Coupled oxidation experiments in the presence of ascorbate indicated that the SARS-CoV-2 glycoprotein can catalyze the slow conversion of heme to biliverdin. The heme trapping and oxidation activities of the spike may allow the virus to reduce levels of free heme during infection to facilitate evasion of the adaptive and innate immunity.

Journal article

Bonnard D, Le Rouzic E, Singer MR, Yu Z, Le Strat F, Batisse C, Batisse J, Amadori C, Chasset S, Pye VE, Emiliani S, Ledoussal B, Ruff M, Moreau F, Cherepanov P, Benarous Ret al., 2023, Biological and Structural Analyses of New Potent Allosteric Inhibitors of HIV-1 Integrase., Antimicrob Agents Chemother, Vol: 67

HIV-1 integrase-LEDGF allosteric inhibitors (INLAIs) share the binding site on the viral protein with the host factor LEDGF/p75. These small molecules act as molecular glues promoting hyper-multimerization of HIV-1 IN protein to severely perturb maturation of viral particles. Herein, we describe a new series of INLAIs based on a benzene scaffold that display antiviral activity in the single digit nanomolar range. Akin to other compounds of this class, the INLAIs predominantly inhibit the late stages of HIV-1 replication. A series of high-resolution crystal structures revealed how these small molecules engage the catalytic core and the C-terminal domains of HIV-1 IN. No antagonism was observed between our lead INLAI compound BDM-2 and a panel of 16 clinical antiretrovirals. Moreover, we show that compounds retained high antiviral activity against HIV-1 variants resistant to IN strand transfer inhibitors and other classes of antiretroviral drugs. The virologic profile of BDM-2 and the recently completed single ascending dose phase I trial (ClinicalTrials.gov identifier: NCT03634085) warrant further clinical investigation for use in combination with other antiretroviral drugs. Moreover, our results suggest routes for further improvement of this emerging drug class.

Journal article

Powell AA, Ireland G, Leeson R, Lacey A, Ford B, Poh J, Ijaz S, Shute J, Cherepanov P, Tedder R, Bottomley C, Dawe F, Mangtani P, Jones P, Nguipdop-Djomo P, Ladhani SN, COVID-19 Schools Infection Survey Groupet al., 2023, National and regional prevalence of SARS-CoV-2 antibodies in primary and secondary school children in England: the School Infection Survey, a national open cohort study, November 2021SARS-CoV-2 antibody prevalence in school children., J Infect, Vol: 86, Pages: 361-368

BACKGROUND: SARS-CoV-2 infection rates are likely to be underestimated in children because of asymptomatic or mild infections. We aim to estimate national and regional prevalence of SARS-CoV-2 antibodies in primary (4-11 years old) and secondary (11-18 years old) school children between 10 November and 10 December 2021. METHODS: Cross-sectional surveillance in England using two-stage sampling, firstly stratifying into regions and selecting local authorities, then selecting schools according to a stratified sample within selected local authorities. Participants were sampled using a novel oral fluid-validated assay for SARS-CoV-2 spike and nucleocapsid IgG antibodies. RESULTS: 4980 students from 117 state-funded schools (2706 from 83 primary schools, 2274 from 34 secondary schools) provided a valid sample. After weighting for age, sex, and ethnicity, and adjusting for assay accuracy, the national prevalence of SARS-CoV-2 antibodies in primary school students, who were all unvaccinated, was 40.1% (95% CI 37.3-43.0). Antibody prevalence increased with age (p < 0.001) and was higher in urban than rural schools (p = 0.01). In secondary school students, the adjusted, weighted national prevalence of SARS-CoV-2 antibodies was 82.4% (95% CI 79.5-85.1); including 71.5% (95% CI 65.7-76.8) in unvaccinated and 97.5% (95% CI 96.1-98.5) in vaccinated students. Antibody prevalence increased with age (p < 0.001), and was not significantly different in urban versus rural students (p = 0.1). CONCLUSIONS: In November 2021, using a validated oral fluid assay, national SARS-CoV-2 seroprevalence was estimated to be 40.1% in primary school students and 82.4% in secondary school students. In unvaccinated children, this was approximately threefold higher than confirmed infections highlighting the importance of seroprevalence studies to estimate prior exposure. DATA AVAILABILITY: Deidentified study data are a

Journal article

Parker E, Thomas J, Roper KJ, Ijaz S, Edwards T, Marchesin F, Katsanovskaja K, Lett L, Jones C, Hardwick HE, Davis C, Vink E, McDonald SE, Moore SC, Dicks S, Jegatheesan K, Cook NJ, Hope J, Cherepanov P, McClure MO, Baillie JK, Openshaw PJM, Turtle L, Ho A, Semple MG, Paxton WA, Tedder RS, Pollakis G, ISARIC4C Investigatorset al., 2023, SARS-CoV-2 antibody responses associate with sex, age and disease severity in previously uninfected people admitted to hospital with COVID-19: An ISARIC4C prospective study, Frontiers in Immunology, Vol: 14, Pages: 1-12, ISSN: 1664-3224

The SARS-CoV-2 pandemic enables the analysis of immune responses induced against a novel coronavirus infecting immunologically naïve individuals. This provides an opportunity for analysis of immune responses and associations with age, sex and disease severity. Here we measured an array of solid-phase binding antibody and viral neutralising Ab (nAb) responses in participants (n=337) of the ISARIC4C cohort and characterised their correlation with peak disease severity during acute infection and early convalescence. Overall, the responses in a Double Antigen Binding Assay (DABA) for antibody to the receptor binding domain (anti-RBD) correlated well with IgM as well as IgG responses against viral spike, S1 and nucleocapsid protein (NP) antigens. DABA reactivity also correlated with nAb. As we and others reported previously, there is greater risk of severe disease and death in older men, whilst the sex ratio was found to be equal within each severity grouping in younger people. In older males with severe disease (mean age 68 years), peak antibody levels were found to be delayed by one to two weeks compared with women, and nAb responses were delayed further. Additionally, we demonstrated that solid-phase binding antibody responses reached higher levels in males as measured via DABA and IgM binding against Spike, NP and S1 antigens. In contrast, this was not observed for nAb responses. When measuring SARS-CoV-2 RNA transcripts (as a surrogate for viral shedding) in nasal swabs at recruitment, we saw no significant differences by sex or disease severity status. However, we have shown higher antibody levels associated with low nasal viral RNA indicating a role of antibody responses in controlling viral replication and shedding in the upper airway. In this study, we have shown discernible differences in the humoral immune responses between males and females and these differences associate with age as well as with resultant disease severity.

Journal article

Singer MR, Dinh T, Levintov L, Annamalai AS, Rey JS, Briganti L, Cook NJ, Pye VE, Taylor IA, Kim K, Engelman AN, Kim B, Perilla JR, Kvaratskhelia M, Cherepanov Pet al., 2023, The Drug-Induced Interface That Drives HIV-1 Integrase Hypermultimerization and Loss of Function., mBio, Vol: 14

Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are an emerging class of small molecules that disrupt viral maturation by inducing the aberrant multimerization of IN. Here, we present cocrystal structures of HIV-1 IN with two potent ALLINIs, namely, BI-D and the drug candidate Pirmitegravir. The structures reveal atomistic details of the ALLINI-induced interface between the HIV-1 IN catalytic core and carboxyl-terminal domains (CCD and CTD). Projecting from their principal binding pocket on the IN CCD dimer, the compounds act as molecular glue by engaging a triad of invariant HIV-1 IN CTD residues, namely, Tyr226, Trp235, and Lys266, to nucleate the CTD-CCD interaction. The drug-induced interface involves the CTD SH3-like fold and extends to the beginning of the IN carboxyl-terminal tail region. We show that mutations of HIV-1 IN CTD residues that participate in the interface with the CCD greatly reduce the IN-aggregation properties of Pirmitegravir. Our results explain the mechanism of the ALLINI-induced condensation of HIV-1 IN and provide a reliable template for the rational development of this series of antiretrovirals through the optimization of their key contacts with the viral target. IMPORTANCE Despite the remarkable success of combination antiretroviral therapy, HIV-1 remains among the major causes of human suffering and loss of life in poor and developing nations. To prevail in this drawn-out battle with the pandemic, it is essential to continue developing advanced antiviral agents to fight drug resistant HIV-1 variants. Allosteric integrase inhibitors (ALLINIs) are an emerging class of HIV-1 antagonists that are orthogonal to the current antiretroviral drugs. These small molecules act as highly specific molecular glue, which triggers the aggregation of HIV-1 integrase. In this work, we present high-resolution crystal structures that reveal the crucial interactions made by two potent ALLINIs, namely, BI-D and Pirmitegravir, with HIV-1 integrase. Our r

Journal article

Lapidus S, Liu F, Casanovas-Massana A, Dai Y, Huck JD, Lucas C, Klein J, Filler RB, Strine MS, Sy M, Deme AB, Badiane AS, Dieye B, Ndiaye IM, Diedhiou Y, Mbaye AM, Diagne CT, Vigan-Womas I, Mbengue A, Sadio BD, Diagne MM, Moore AJ, Mangou K, Diallo F, Sene SD, Pouye MN, Faye R, Diouf B, Nery N, Costa F, Reis MG, Muenker MC, Hodson DZ, Mbarga Y, Katz BZ, Andrews JR, Campbell M, Srivathsan A, Kamath K, Baum-Jones E, Faye O, Sall AA, Velez JCQ, Cappello M, Wilson M, Ben-Mamoun C, Tedder R, McClure M, Cherepanov P, Some FA, Dabire RK, Moukoko CEE, Ouedraogo JB, Boum Y, Shon J, Ndiaye D, Wisnewski A, Parikh S, Iwasaki A, Wilen CB, Ko A, Ring AM, Bei AKet al., 2022, Plasmodium infection is associated with cross-reactive antibodies to carbohydrate epitopes on the SARS-CoV-2 Spike protein, SCIENTIFIC REPORTS, Vol: 12, ISSN: 2045-2322

Journal article

van Vliet AR, Chiduza GN, Maslen SL, Pye VE, Joshi D, De Tito S, Jefferies HBJ, Christodoulou E, Roustan C, Punch E, Hervas JH, O'Reilly N, Skehel JM, Cherepanov P, Tooze SAet al., 2022, ATG9A and ATG2A form a heteromeric complex essential for autophagosome formation, MOLECULAR CELL, Vol: 82, Pages: 4324-+, ISSN: 1097-2765

Journal article

Seow J, Khan H, Rosa A, Calvares V, Graham C, Pickering S, Pye VE, Cronin NB, Huettner I, Malim MH, Politis A, Cherepanov P, Doores KJet al., 2022, A neutralizing epitope on the SD1 domain of SARS-CoV-2 spike targeted following infection and vaccination, CELL REPORTS, Vol: 40, ISSN: 2211-1247

Journal article

Jozwik IK, Li W, Zhang D-W, Wong D, Grawenhoff J, Ballandras-Colas A, Aiyer S, Cherepanov P, Engelman AN, Lyumkis Det al., 2022, B-to-A transition in target DNA during retroviral integration, NUCLEIC ACIDS RESEARCH, Vol: 50, Pages: 8898-8918, ISSN: 0305-1048

Journal article

Ng KW, Faulkner N, Finsterbusch K, Wu M, Harvey R, Hussain S, Greco M, Liu Y, Kjaer S, Swanton C, Gandhi S, Beale R, Gamblin SJ, Cherepanov P, McCauley J, Daniels R, Howell M, Arase H, Wack A, Bauer DL, Kassiotis Get al., 2022, SARS-CoV-2 S2-targeted vaccination elicits broadly neutralizing antibodies, SCIENCE TRANSLATIONAL MEDICINE, Vol: 14, ISSN: 1946-6234

Journal article

Ijaz S, Dicks S, Jegatheesan K, Parker E, Katsanovskaja K, Vink E, McClure MO, Shute J, Hope J, Cook N, Cherepanov P, Turtle L, Paxton WA, Pollakis G, Ho A, Openshaw PJM, Baillie JK, Semple MG, Tedder RS, for ISARIC4C Investigatorset al., 2022, Mapping of SARS-CoV-2 IgM and IgG in gingival crevicular fluid: antibody dynamics and linkage to severity of COVID-19 in hospital inpatients, Journal of Infection, Vol: 85, Pages: 152-160, ISSN: 0163-4453

Journal article

Ballandras-Colas A, Chivukula V, Gruszka DT, Shan Z, Singh PK, Pye VE, McLean RK, Bedwell GJ, Li W, Nans A, Cook NJ, Fadel HJ, Poeschla EM, Griffiths DJ, Vargas J, Taylor IA, Lyumkis D, Yardimci H, Engelman AN, Cherepanov Pet al., 2022, Multivalent interactions essential for lentiviral integrase function, NATURE COMMUNICATIONS, Vol: 13

Journal article

Khan M, Rosadas C, Katsanovskaja K, Weber ID, Shute J, Ijaz S, Marchesin F, McClure E, Elias S, Flower B, Gao H, Quinlan R, Short C, Rosa A, Roustan C, Moshe M, Taylor GP, Elliott P, Cooke GS, Cherepanov P, Parker E, McClure MO, Tedder RSet al., 2022, Simple, sensitive, specific self-sampling assay secures SARS-CoV-2 antibody signals in sero-prevalence and post-vaccine studies, Scientific Reports, Vol: 12, ISSN: 2045-2322

At-home sampling is key to large scale seroprevalence studies. Dried blood spot (DBS) self-sampling removes the need for medical personnel for specimen collection but facilitates specimen referral to an appropriately accredited laboratory for accurate sample analysis. To establish a highly sensitive and specific antibody assay that would facilitate self-sampling for prevalence and vaccine-response studies. Paired sera and DBS eluates collected from 439 sero-positive, 382 sero-negative individuals and DBS from 34 vaccine recipients were assayed by capture ELISAs for IgG and IgM antibody to SARS-CoV-2. IgG and IgM combined on DBS eluates achieved a diagnostic sensitivity of 97.9% (95%CI 96.6 to 99.3) and a specificity of 99.2% (95% CI 98.4 to 100) compared to serum, displaying limits of detection equivalent to 23 and 10 WHO IU/ml, respectively. A strong correlation (r = 0.81) was observed between serum and DBS reactivities. Reactivity remained stable with samples deliberately rendered inadequate, (p = 0.234) and when samples were accidentally damaged or 'invalid'. All vaccine recipients were sero-positive. This assay provides a secure method for self-sampling by DBS with a sensitivity comparable to serum. The feasibility of DBS testing in sero-prevalence studies and in monitoring post-vaccine responses was confirmed, offering a robust and reliable tool for serological monitoring at a population level.

Journal article

Rosadas C, Khan M, Parker E, Marchesin F, Katsanovskaja K, Sureda-Vives M, Fernandez N, Randell P, Harvey R, Lilley A, Harris BH, Zuhair M, Fertleman M, Ijaz S, Dicks S, Short C-E, Quinlan R, Taylor GP, Hu K, McKay P, Rosa A, Roustan C, Zuckerman M, El Bouzidi K, Cooke G, Flower B, Moshe M, Elliott P, Spencer AJ, Lambe T, Gilbert SC, Kingston H, Baillie JK, Openshaw PJ, G Semple M, ISARIC4C Investigators, Cherepanov P, O McClure M, S Tedder Ret al., 2022, Detection and quantification of antibody to SARS CoV 2 receptor binding domain provides enhanced sensitivity, specificity and utility, Journal of Virological Methods, Vol: 302, ISSN: 0166-0934

Accurate and sensitive detection of antibody to SARS-CoV-2 remains an essential component of the pandemic response. Measuring antibody that predicts neutralising activity and the vaccine response is an absolute requirement for laboratory-based confirmatory and reference activity. The viral receptor binding domain (RBD) constitutes the prime target antigen for neutralising antibody. A double antigen binding assay (DABA), providing the most sensitive format has been exploited in a novel hybrid manner employing a solid-phase S1 preferentially presenting RBD, coupled with a labelled RBD conjugate, used in a two-step sequential assay for detection and measurement of antibody to RBD (anti-RBD). This class and species neutral assay showed a specificity of 100% on 825 pre COVID-19 samples and a potential sensitivity of 99.6% on 276 recovery samples, predicting quantitatively the presence of neutralising antibody determined by pseudo-type neutralisation and by plaque reduction. Anti-RBD is also measurable in ferrets immunised with ChadOx1 nCoV-19 vaccine and in humans immunised with both AstraZeneca and Pfizer vaccines. This assay detects anti-RBD at presentation with illness, demonstrates its elevation with disease severity, its sequel to asymptomatic infection and its persistence after the loss of antibody to the nucleoprotein (anti-NP). It also provides serological confirmation of prior infection and offers a secure measure for seroprevalence and studies of vaccine immunisation in human and animal populations. The hybrid DABA also displays the attributes necessary for the detection and quantification of anti-RBD to be used in clinical practice. An absence of detectable anti-RBD by this assay predicates the need for passive immune prophylaxis in at-risk patients.

Journal article

Maertens GN, Engelman AN, Cherepanov P, 2022, Structure and function of retroviral integrase, Nature Reviews Microbiology, Vol: 20, Pages: 20-34, ISSN: 1740-1526

A hallmark of retroviral replication is establishment of the proviral state, wherein a DNA copy of the viral RNA genome is stably incorporated into a host cell chromosome. Integrase is the viral enzyme responsible for the catalytic steps involved in this process, and integrase strand transfer inhibitors are widely used to treat people living with HIV. Over the past decade, a series of X-ray crystallography and cryogenic electron microscopy studies have revealed the structural basis of retroviral DNA integration. A variable number of integrase molecules congregate on viral DNA ends to assemble a conserved intasome core machine that facilitates integration. The structures additionally informed on the modes of integrase inhibitor action and the means by which HIV acquires drug resistance. Recent years have witnessed the development of allosteric integrase inhibitors, a highly promising class of small molecules that antagonize viral morphogenesis. In this Review, we explore recent insights into the organization and mechanism of the retroviral integration machinery and highlight open questions as well as new directions in the field.

Journal article

Davis C, Logan N, Tyson G, Orton R, Harvey WT, Perkins JS, Mollett G, Blacow RM, Peacock TP, Barclay WS, Cherepanov P, Palmarini M, Murcia PR, Patel AH, Robertson DL, Haughney J, Thomson EC, Willett BJet al., 2021, Reduced neutralisation of the Delta (B.1.617.2) SARS-CoV-2 variant of concern following vaccination, PLOS PATHOGENS, Vol: 17, ISSN: 1553-7366

Journal article

Alrubayyi A, Gea-Mallorqui E, Touizer E, Hameiri-Bowen D, Kopycinski J, Charlton B, Fisher-Pearson N, Muir L, Rosa A, Roustan C, Earl C, Cherepanov P, Pellegrino P, Waters L, Burns F, Kinloch S, Dong T, Dorrell L, Rowland-Jones S, McCoy LE, Peppa Det al., 2021, Characterization of humoral and SARS-CoV-2 specific T cell responses in people living with HIV, NATURE COMMUNICATIONS, Vol: 12

Journal article

Barski MS, Vanzo T, Zhao XZ, Smith SJ, Ballandras-Colas A, Cronin NB, Pye VE, Hughes SH, Burke TR, Cherepanov P, Maertens GNet al., 2021, Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures (vol 12, 4996, 2021), NATURE COMMUNICATIONS, Vol: 12

Journal article

Cherepanov P, 2021, The KT Jeang Retrovirology prize 2021: Peter Cherepanov, RETROVIROLOGY, Vol: 18

Journal article

Arulkumaran N, Snow TAC, Kulkarni A, Brealey D, Rickman HM, Rees-Spear C, Spyer MJ, Heaney J, Garr E, Williams B, Cherepanov P, Kassiotis G, Lunn MP, Ambler G, Houlihan C, McCoy LE, Nastouli E, Singer Met al., 2021, Influence of IL-6 levels on patient survival in COVID-19, JOURNAL OF CRITICAL CARE, Vol: 66, Pages: 123-125, ISSN: 0883-9441

Journal article

Deakin CT, Cornish GH, Ng KW, Faulkner N, Bolland W, Hope J, Rosa A, Harvey R, Hussain S, Earl C, Jebson BR, Wilkinson MGLL, Marshall LR, O'Brien K, Rosser EC, Radziszewska A, Peckham H, Patel H, Heaney J, Rickman H, Paraskevopoulou S, Houlihan CF, Spyer MJ, Gamblin SJ, McCauley J, Nastouli E, Levin M, Cherepanov P, Ciurtin C, Wedderburn LR, Kassiotis Get al., 2021, Favorable antibody responses to human coronaviruses in children and adolescents with autoimmune rheumatic diseases, MED, Vol: 2, Pages: 1093-+, ISSN: 2666-6340

Journal article

Maertens G, Barski MS, Vanzo T, Zhao X, Smith SJ, Ballandras-Colas A, Cronin NB, Pye VE, Hughes SH, Burke TRJ, Cherepanov Pet al., 2021, Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures, Nature Communications, Vol: 12, Pages: 1-10, ISSN: 2041-1723

Between 10 and 20 million people worldwide are infected with the human T-celllymphotropic virus type 1 (HTLV-1). Despite causing life-threateningpathologies there is no therapeutic regimen for this deltaretrovirus. Here, wescreened a library of integrase strand transfer inhibitor (INSTI) candidates builtaround several chemical scaffolds to determine their effectiveness in limitingHTLV-1 infection. Naphthyridines with substituents in position 6 emerged as themost potent compounds against HTLV-1, with XZ450 having highest efficacy invitro. Using single-particle cryo-electron microscopy we visualised XZ450 aswell as the clinical HIV-1 INSTIs raltegravir and bictegravir bound to the activesite of the deltaretroviral intasome. The structures reveal subtle differences inthe coordination environment of the Mg2+ ion pair involved in the interactionwith the INSTIs. Our results elucidate the binding of INSTIs to the HTLV-1intasome and support their use for pre-exposure prophylaxis and possiblyfuture treatment of HTLV-1 infection.

Journal article

Arulkumaran N, Snow TAC, Kulkarni A, Brealey D, Rickman H, Rees-Spear C, Spyer MJ, Heaney J, Garr E, Williams B, Cherepanov P, Kassiotis G, Lunn M, Houlihan C, McCoy LE, Nastouli E, Singer Met al., 2021, Defining Potential Therapeutic Targets in Coronavirus Disease 2019: A Cross-Sectional Analysis of a Single-Center Cohort., Crit Care Explor, Vol: 3

OBJECTIVES: Multiple mechanisms have been proposed to explain disease severity in coronavirus disease 2019. Therapeutic approaches need to be underpinned by sound biological rationale. We evaluated whether serum levels of a range of proposed coronavirus disease 2019 therapeutic targets discriminated between patients with mild or severe disease. DESIGN: A search of ClinicalTrials.gov identified coronavirus disease 2019 immunological drug targets. We subsequently conducted a retrospective observational cohort study investigating the association of serum biomarkers within the first 5 days of hospital admission relating to putative therapeutic biomarkers with illness severity and outcome. SETTING: University College London, a tertiary academic medical center in the United Kingdom. PATIENTS: Patients admitted to hospital with a diagnosis of coronavirus disease 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty-six patients were recruited, 44 (51%) with mild disease and 42 (49%) with severe disease. We measured levels of 10 cytokines/signaling proteins related to the most common therapeutic targets (granulocyte-macrophage colony-stimulating factor, interferon-α2a, interferon-β, interferon-γ, interleukin-1β, interleukin-1 receptor antagonist, interleukin-6, interleukin-7, interleukin-8, tumor necrosis factor-α), immunoglobulin G antibodies directed against either coronavirus disease 2019 spike protein or nucleocapsid protein, and neutralization titers of antibodies. Four-hundred seventy-seven randomized trials, including 168 different therapies against 83 different pathways, were identified. Six of the 10 markers (interleukin-6, interleukin-7, interleukin-8, interferon-α2a, interferon-β, interleukin-1 receptor antagonist) discriminated between patients with mild and severe disease, although most were similar or only modestly raised above that seen in healthy volunteers. A similar proportion of patients with mild or sever

Journal article

Arulkumaran N, Snow TAC, Kulkarni A, Brealey D, Rickman HM, Rees-Spear C, Spyer MJ, Heaney J, Garr E, Williams B, Cherepanov P, Kassiotis G, Lunn MP, Houlihan C, McCoy LE, Nastouli E, Singer Met al., 2021, Sex differences in immunological responses to COVID-19: a cross-sectional analysis of a single-centre cohort, BRITISH JOURNAL OF ANAESTHESIA, Vol: 127, Pages: E75-E78, ISSN: 0007-0912

Journal article

Muir L, Jaffer A, Rees-Spear C, Gopalan V, Chang FY, Fernando R, Vaitkute G, Roustan C, Rosa A, Earl C, Rajakaruna GK, Cherepanov P, Salama A, McCoy LE, Motallebzadeh Ret al., 2021, Neutralizing Antibody Responses After SARS-CoV-2 Infection in End-Stage Kidney Disease and Protection Against Reinfection, KIDNEY INTERNATIONAL REPORTS, Vol: 6, Pages: 1799-1809, ISSN: 2468-0249

Journal article

Davis C, Logan N, Tyson G, Orton R, Harvey W, Haughney J, Perkins J, Peacock TP, Barclay WS, Cherepanov P, Palmarini M, Murcia PR, Patel AH, Robertson DL, Thomson EC, Willett BJet al., 2021, Reduced neutralisation of the Delta (B.1.617.2) SARS-CoV-2 variant of concern following vaccination

<jats:title>Abstract</jats:title><jats:p>Vaccines are proving to be highly effective in controlling hospitalisation and deaths associated with SARS-CoV-2 infection but the emergence of viral variants with novel antigenic profiles threatens to diminish their efficacy. Assessment of the ability of sera from vaccine recipients to neutralise SARS-CoV-2 variants will inform the success of strategies for minimising COVID19 cases and the design of effective antigenic formulations. Here, we examine the sensitivity of variants of concern (VOCs) representative of the B.1.617.1 and B.1.617.2 (first associated with infections in India) and B.1.351 (first associated with infection in South Africa) lineages of SARS-CoV-2 to neutralisation by sera from individuals vaccinated with the BNT162b2 (Pfizer/BioNTech) and ChAdOx1 (Oxford/AstraZeneca) vaccines. Across all vaccinated individuals, the spike glycoproteins from B.1.617.1 and B.1.617.2 conferred reductions in neutralisation of 4.31 and 5.11-fold respectively. The reduction seen with the B.1.617.2 lineage approached that conferred by the glycoprotein from B.1.351 (South African) variant (6.29-fold reduction) that is known to be associated with reduced vaccine efficacy. Neutralising antibody titres elicited by vaccination with two doses of BNT162b2 were significantly higher than those elicited by vaccination with two doses of ChAdOx1. Fold decreases in the magnitude of neutralisation titre following two doses of BNT162b2, conferred reductions in titre of 7.77, 11.30 and 9.56-fold respectively to B.1.617.1, B.1.617.2 and B.1.351 pseudoviruses, the reduction in neutralisation of the delta variant B.1.617.2 surpassing that of B.1.351. Fold changes in those vaccinated with two doses of ChAdOx1 were 0.69, 4.01 and 1.48 respectively. The accumulation of mutations in these VOCs, and others, demonstrate the quantifiable risk of antigenic drift and subsequent reduction in vaccine efficacy. Accordingly, booster vaccines b

Journal article

Graham C, Seow J, Huettner I, Khan H, Kouphou N, Acors S, Winstone H, Pickering S, Galao RP, Dupont L, Lista MJ, Jimenez-Guardeno JM, Laing AG, Wu Y, Joseph M, Muir L, van Gils MJ, Ng WM, Duyvesteyn HME, Zhao Y, Bowden TA, Shankar-Hari M, Rosa A, Cherepanov P, McCoy LE, Hayday AC, Neil SJD, Malim MH, Doores KJet al., 2021, Neutralization potency of monoclonal antibodies recognizing dominant and subdominant epitopes on SARS-CoV-2 Spike is impacted by the B.1.1.7 variant, IMMUNITY, Vol: 54, Pages: 1276-+, ISSN: 1074-7613

Journal article

Hodakova Z, Nans A, Kunzelmann S, Mehmood S, Taylor I, Uhlmann F, Cherepanov P, Singleton MRet al., 2021, Structural characterisation of the Chaetomium thermophilum Chl1 helicase, PLOS ONE, Vol: 16, ISSN: 1932-6203

Journal article

Rosa A, Pye VE, Graham C, Muir L, Seow J, Ng KW, Cook NJ, Rees-Spear C, Parker E, dos Santos MS, Rosadas C, Susana A, Rhys H, Nans A, Masino L, Roustan C, Christodoulou E, Ulferts R, Wrobel AG, Short C-E, Fertleman M, Sanders RW, Heaney J, Spyer M, Kjaer S, Riddell A, Malim MH, Beale R, MacRae J, Taylor GP, Nastouli E, van Gils MJ, Rosenthal PB, Pizzato M, McClure MO, Tedder RS, Kassiotis G, McCoy LE, Doores KJ, Cherepanov Pet al., 2021, SARS-CoV-2 can recruit a heme metabolite to evade antibody immunity, Science Advances, Vol: 7, Pages: 1-14, ISSN: 2375-2548

The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of heme metabolism, with nanomolar affinity. Using cryo–electron microscopy and x-ray crystallography, we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that SARS-CoV-2 spike NTD harbors a dominant epitope, access to which can be controlled by an allosteric mechanism that is regulated through recruitment of a metabolite.

Journal article

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