DOCSLIB.ORG

SAMHD1 . . . and Viral Ways Around It

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
SAMHD1 . . . and Viral Ways Around It viruses Review SAMHD1 . and Viral Ways around It Janina Deutschmann and Thomas Gramberg * Institute of Clinical and Molecular Virology, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany; [email protected] * Correspondence: [email protected] Abstract: The SAM and HD domain-containing protein 1 (SAMHD1) is a dNTP triphosphohydrolase that plays a crucial role for a variety of different cellular functions. Besides balancing intracellular dNTP concentrations, facilitating DNA damage repair, and dampening excessive immune responses, SAMHD1 has been shown to act as a major restriction factor against various virus species. In addition to its well-described activity against retroviruses such as HIV-1, SAMHD1 has been identified to reduce the infectivity of different DNA viruses such as the herpesviruses CMV and EBV, the poxvirus VACV, or the hepadnavirus HBV. While some viruses are efficiently restricted by SAMHD1, others have developed evasion mechanisms that antagonize the antiviral activity of SAMHD1. Within this review, we summarize the different cellular functions of SAMHD1 and highlight the countermeasures viruses have evolved to neutralize the restriction factor SAMHD1. Keywords: SAMHD1; restriction factor; viral antagonism; HIV; herpesviruses; viral kinases; Vpx; dNTP hydrolase; viral interference 1. The dNTPase SAMHD1 The SAM and HD domain-containing protein 1 (SAMHD1) is a ubiquitously expressed Citation: Deutschmann, J.; deoxynucleotide triphosphohydrolase (dNTPase) of 626 amino acids (Figure1). In general, Gramberg, T. SAMHD1 . and Viral sterile alpha motif (SAM) domains have been shown to mediate protein–protein interaction Ways around It. Viruses 2021, 13, 395. or nucleic acid binding; however, its function in SAMHD1 is still unclear. The enzymatically https://doi.org/10.3390/v13030395 active HD domain, defined by two pairs of histidine and aspartate residues in its active center, on the other hand is essential for retroviral restriction and tetramerization of the Academic Editor: Sébastien Nisole protein [1–3]. Although nuclear localization of SAMHD1 is mediated through an N- terminal nuclear localization signal (NLS), neither the antiviral activity nor the dNTPase Received: 12 February 2021 function of SAMHD1 seem to be influenced by its localization [4–6]. Oligomerization Accepted: 25 February 2021 of SAMHD1 is required for its catalytic dNTPase activity and is induced upon cofactor Published: 2 March 2021 binding at two allosteric sites within the protein [7–12]. At allosteric site 1, dGTP or GTP binding leads to SAMHD1 dimerization, while the subsequent binding of any dNTP to Publisher’s Note: MDPI stays neutral allosteric site 2 induces tetramer formation [1,13,14]. with regard to jurisdictional claims in SAMHD1 converts dNTPs into deoxynucleosides (dN) and inorganic triphosphates published maps and institutional affil- (PPPi) and thereby counteracts the de novo dNTP synthesis, primarily conducted by iations. ribonucleotide reductase (RNR) and cellular deoxynucleoside kinases, which are mainly active during the S phase of the cell cycle [15–18]. RNR catalyzes the formation of dNTPs from ribonucleotides, while deoxynucleoside kinases, such as thymidine kinases (TK), add phosphates to nucleosides to form deoxynucleoside triphosphates [19,20]. This ensures Copyright: © 2021 by the authors. a highly balanced dNTP pool during the progression of the cell cycle, with a sufficient Licensee MDPI, Basel, Switzerland. supply of dNTPs for efficient genome replication in dividing cells and limited levels of This article is an open access article dNTPs in nondividing and resting cells [1,14,21]. The cyclin-dependent kinases (CDK) 1 distributed under the terms and and 2, together with cyclin A, phosphorylate SAMHD1 at the threonine residue 592 (T592) conditions of the Creative Commons Attribution (CC BY) license (https:// during the S and G2 phase of the cell cycle [22,23]. SAMHD1 is dephosphorylated during α creativecommons.org/licenses/by/ the M/G1 phase transition by the PP2A-B55 phosphatase and is dephosphorylated in the 4.0/). G0 and G1 phases [24]. Thus, SAMHD1 is phosphorylated during the progression of the Viruses 2021, 13, 395. https://doi.org/10.3390/v13030395 https://www.mdpi.com/journal/viruses Viruses 2021, 13, x FOR PEER REVIEW 2 of 16 Viruses 2021, 13, 395 2 of 16 dephosphorylated during the M/G1 phase transition by the PP2A-B55α phosphatase and is dephosphorylated in the G0 and G1 phases [24]. Thus, SAMHD1 is phosphorylated cellduring cycle, the which progression correlates of the with cell the cycle, demand which of cellularcorrelates dNTPs. with However,the demand at thisof cellular pointit isdNTPs. unclear However, whether at the this phosphorylation point it is unclear at T592whether indeed the regulatesphosphorylation the dNTPase at T592 activity indeed of SAMHD1regulates the [25 –dNTPase28]. activity of SAMHD1 [25–28]. FigureFigure 1. 1.Cellular Cellular functionsfunctions ofof SAMHD1.SAMHD1. The dNTP triphosphohydrolase SAMHD1 SAMHD1 is is an an important important regulator regulator of of dNTP dNTP levels. A correct balance of the cellular dNTP pool has been shown to be important for cell-cycle control and genome levels. A correct balance of the cellular dNTP pool has been shown to be important for cell-cycle control and genome integrity. SAMHD1 is a mediator of double-strand break (DSB) repair and ensures the progression of DNA replication. integrity. SAMHD1 is a mediator of double-strand break (DSB) repair and ensures the progression of DNA replication. Mutations in the SAMHD1 gene have been identified in various types of cancer. Furthermore, SAMHD1 potently restricts Mutationsviral infectivity in the SAMHD1of retrovirusesgene haveand DNA been identifiedviruses, and in variousblocks the types activity of cancer. of endogenous Furthermore, retroelements. SAMHD1 potently Mutations restricts in viralSAMHD1 infectivity are correlated of retroviruses with autoimmune and DNA viruses,diseases andsuch blocksas Aicardi–Goutières the activity of syndrome, endogenous resulting retroelements. in elevated Mutations type I IFN in SAMHD1levels. SAMHD1are correlated also impairs with autoimmune the innate immune diseases sensing such asof Aicardi–Goutiviral infectionsè resby interfering syndrome, with resulting cGAS/STING in elevated nucleic type acid I IFN levels.recognition SAMHD1 and NF alsoκB/IRF impairs signaling the innate pathways. immune sensing of viral infections by interfering with cGAS/STING nucleic acid recognition and NFκB/IRF signaling pathways. 2. DNA Replication and DNA Damage Repair 2. DNA Replication and DNA Damage Repair By degrading cellular dNTPs, SAMHD1 is a major regulator of nucleotide homeostasis.By degrading A highly cellular balanced dNTPs, dNTP SAMHD1 pool is aessential major regulator for genomic of nucleotide integrity, homeostasis. including Aproper highly DNA balanced replication dNTP and pool efficient is essential repair for of genomicDNA breaks. integrity, An imbalance including can proper lead DNAto a replicationderegulated and cell-cycle efficient progression repair of DNAand therefore breaks. Aninduce imbalance replication can leadstress, to awhich deregulated might cell-cycleeventually progression result in the andaccumulation therefore induceof genomic replication mutations stress, [29,30]. which During might host eventually genome resultreplication, in the SAMHD1 accumulation was offound genomic to be mutations recruited [ 29to, 30replication]. During foci host to genome regulate replica- the tion,progression SAMHD1 of the was replication found to fork. be recruited Here, SAMHD1 to replication activates foci the to 3′ regulate-5′-exonuclease the progression MRE11, 0 0 ofthereby the replication promoting fork. the Here, MRE11-mediated SAMHD1 activates degradation the 3 -5 of-exonuclease nascent DNA MRE11, at stalled thereby promotingreplication theforks, MRE11-mediated which has been degradationsuggested to ofprevent nascent the DNA induction at stalled of type replication I interferons forks, which(IFN) through has been the suggested aberrant toaccumulation prevent the of induction single-stranded of type DNA I interferons (ssDNA). (IFN) In addition, through thestimulation aberrant of accumulation MRE11 by SAMHD1 of single-stranded leads to DNAactivation (ssDNA). of the In ATR-CHK1 addition, stimulation checkpoint, of MRE11resulting by in SAMHD1 restart and leads progression to activation of stalled of the replication ATR-CHK1 forks checkpoint, [31]. resulting in restart and progressionSAMHD1 has of stalledalso been replication described forks to [31be]. important for DNA damage repair by promotingSAMHD1 homologous has also beenrecombination described (HR) to be [32]. important SAMHD1 for was DNA identified damage to repair localize by pro-to motingDNA double-strand homologous recombinationbreaks (DSBs) (HR)and [to32 ].recruit SAMHD1 members was identifiedof the DSB to localizerepair (DSBR) to DNA double-strandmachinery [32,33]. breaks It directly (DSBs) binds and to to recruit the C-terminal members binding of the DSBprotein repair interacting (DSBR) protein machin- ery(CtIP), [32 ,leading33]. It directly to its recruitment binds to the to C-terminalDSBs and consequently binding protein to the interacting activation protein of MRE11 (CtIP), as leadingpart of tothe its MRE11-Rad50-NBS1 recruitment to DSBs (MRN) and consequently DSBR complex, to the which activation is responsible of MRE11 asfor part the of theresection MRE11-Rad50-NBS1
Load more

Recommended publications
  • DMD #9209 1 N-Methylpurine DNA Glycosylase and 8-Oxoguanine
    DMD Fast Forward. Published on March 24, 2006 as DOI: 10.1124/dmd.105.009209 DMD FastThis article Forward. has not beenPublished copyedited on and March formatted. 24, The 2006 final version as doi:10.1124/dmd.105.009209 may differ from this version. DMD #9209 N-methylpurine DNA glycosylase and 8-oxoguanine DNA glycosylase metabolize the antiviral nucleoside 2-bromo-5,6-dichloro-1-(β-D-ribofuranosyl)benzimidazole Philip L. Lorenzi1, Christopher P. Landowski2, Andrea Brancale, Xueqin Song, Leroy B. Townsend, John C. Drach and Gordon L. Amidon. Department of Pharmaceutical Sciences (P.L.L., C.P.L., X.S., G.L.A.) and Medicinal Chemistry (L.B.T., J.C.D.), College of Pharmacy, and Department of Biologic and Downloaded from Materials Sciences (J.C.D.), School of Dentistry, University of Michigan, Ann Arbor, Michigan, USA; and Welsh School of Pharmacy (A.B.), Cardiff University, Wales, UK. dmd.aspetjournals.org at ASPET Journals on September 24, 2021 1 Copyright 2006 by the American Society for Pharmacology and Experimental Therapeutics. DMD Fast Forward. Published on March 24, 2006 as DOI: 10.1124/dmd.105.009209 This article has not been copyedited and formatted. The final version may differ from this version. DMD #9209 Running Title: Nucleoside drug metabolism by DNA repair enzymes Text pages: 19 Tables: 4 Figures: 3 References: 43 Words in Abstract: 180 Words in Introduction: 464 Words in Discussion: 1433 Abbreviations: BDCRB, 2-bromo-5,6-dichloro-1-(β-D-ribofuranosyl)benzimidazole; TCRB, 2,5,6-trichloro-1-(β-D-ribofuranosyl)benzimidazole;
    [Show full text]
  • Novel Therapeutics for Epstein–Barr Virus
    molecules Review Novel Therapeutics for Epstein–Barr Virus Graciela Andrei *, Erika Trompet and Robert Snoeck Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium; [email protected] (E.T.); [email protected] (R.S.) * Correspondence: [email protected]; Tel.: +32-16-321-915 Academic Editor: Stefano Aquaro Received: 15 February 2019; Accepted: 4 March 2019; Published: 12 March 2019 Abstract: Epstein–Barr virus (EBV) is a human γ-herpesvirus that infects up to 95% of the adult population. Primary EBV infection usually occurs during childhood and is generally asymptomatic, though the virus can cause infectious mononucleosis in 35–50% of the cases when infection occurs later in life. EBV infects mainly B-cells and epithelial cells, establishing latency in resting memory B-cells and possibly also in epithelial cells. EBV is recognized as an oncogenic virus but in immunocompetent hosts, EBV reactivation is controlled by the immune response preventing transformation in vivo. Under immunosuppression, regardless of the cause, the immune system can lose control of EBV replication, which may result in the appearance of neoplasms. The primary malignancies related to EBV are B-cell lymphomas and nasopharyngeal carcinoma, which reflects the primary cell targets of viral infection in vivo. Although a number of antivirals were proven to inhibit EBV replication in vitro, they had limited success in the clinic and to date no antiviral drug has been approved for the treatment of EBV infections. We review here the antiviral drugs that have been evaluated in the clinic to treat EBV infections and discuss novel molecules with anti-EBV activity under investigation as well as new strategies to treat EBV-related diseases.
    [Show full text]
  • Clinical Development of Letermovir and Maribavir Overview of Human
    Antiviral Research 163 (2019) 91–105 Contents lists available at ScienceDirect Antiviral Research journal homepage: www.elsevier.com/locate/antiviral Clinical development of letermovir and maribavir: Overview of human T cytomegalovirus drug resistance ∗ Jocelyne Piret, Guy Boivin Research Center in Infectious Diseases, CHU of Quebec and Laval University, Quebec City, QC, Canada ARTICLE INFO ABSTRACT Keywords: The prevention and treatment of human cytomegalovirus (HCMV) infections is based on the use of antiviral Human cytomegalovirus agents that currently target the viral DNA polymerase and that may cause serious side effects. The search for Letermovir novel inhibitors against HCMV infection led to the discovery of new molecular targets, the viral terminase Maribavir complex and the viral pUL97 kinase. The most advanced compounds consist of letermovir (LMV) and maribavir Drug resistance (MBV). LMV inhibits the cleavage of viral DNA and its packaging into capsids by targeting the HCMV terminase Viral terminase complex complex. LMV is safe and well tolerated and exhibits pharmacokinetic properties that allow once daily dosing. Viral pUL97 kinase LMV showed efficacy in a phase III prophylaxis study in hematopoietic stem cell transplant (HSCT) recipients seropositive for HCMV. LMV was recently approved under the trade name Prevymis™ for prophylaxis of HCMV infection in adult seropositive recipients of an allogeneic HSCT. Amino acid substitutions conferring resistance to LMV selected in vitro map primarily to the pUL56 and rarely to the pUL89 and pUL51 subunits of the HCMV terminase complex. MBV is an inhibitor of the viral pUL97 kinase activity and interferes with the morphogenesis and nuclear egress of nascent viral particles. MBV is safe and well tolerated and has an excellent oral bioa- vailability.
    [Show full text]
  • Investigating Synergy Between Ribonucleotide Reductase Inhibitors and Cmv Antivirals
    Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2012 INVESTIGATING SYNERGY BETWEEN RIBONUCLEOTIDE REDUCTASE INHIBITORS AND CMV ANTIVIRALS Sukhada Bhave Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Medicine and Health Sciences Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/2838 This Thesis is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. © Sukhada Milind Bhave August 2012 All Rights Reserved INVESTIGATING SYNERGY BETWEEN RIBONUCLEOTIDE REDUCTASE INHIBITORS AND CMV ANTIVIRALS A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University. by Sukhada Milind Bhave Bachelor of Pharmacy, Bombay College of Pharmacy, India, 2010 Major Director: Michael McVoy, Ph.D. Professor, Department of Microbiology and Immunology Virginia Commonwealth University Richmond, Virginia August 2012 ACKNOWLEDGEMENTS It is a pleasure to thank everyone who made this thesis possible. First, I would like to thank Dr. McVoy for accepting me as a graduate student in his lab and for his guidance and support through this project. I would also like to thank the other members of the McVoy lab: Frances Saccoccio, Anne Sauer, Xiao Cui, Ronzo Lee, Ben Wang, and Sabrina Prescott for sharing their expertise and helping me through various steps in the project. All of them indeed create a very cheerful and pleasant atmosphere in the lab.
    [Show full text]
  • The Third International Consensus Guidelinesthe on Management of Cytomegalovirus in Cincinnati, OH
    Original Clinical ScienceçGeneral The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation Camille N. Kotton, MD,1 Deepali Kumar, MD,2 Angela M. Caliendo, MD, PhD,3 Shirish Huprikar, MD,4 01/28/2019 on BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3pzrw1VmaZXQ+S1X5qzIxw8+AIlXMhR5CNF7trXzV+w4= by https://journals.lww.com/transplantjournal from Downloaded Sunwen Chou, MD,5 Lara Danziger-Isakov, MD, MPH,6 and Atul Humar, MD7 Downloaded on behalf of the The Transplantation Society International CMV Consensus Group from https://journals.lww.com/transplantjournal Abstract: Despite recent advances, cytomegalovirus (CMV) infections remain one of the most common complications affecting solid organ transplant recipients, conveying higher risks of complications, graft loss, morbidity, and mortality. Research in the field and development of prior consensus guidelines supported by The Transplantation Society has allowed a more standardized ap- proach to CMV management. An international multidisciplinary panel of experts was convened to expand and revise evidence and expert opinion-based consensus guidelines on CMV management including prevention, treatment, diagnostics, immunology, drug resistance, and pediatric issues. Highlights include advances in molecular and immunologic diagnostics, improved understanding by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3pzrw1VmaZXQ+S1X5qzIxw8+AIlXMhR5CNF7trXzV+w4= of diagnostic thresholds, optimized methods of prevention, advances in the use of novel antiviral therapies and certain immuno- suppressive agents, and more savvy approaches to treatment resistant/refractory disease. The following report summarizes the updated recommendations. (Transplantation 2018;102: 900–931) he past 5 years has seen exciting advances related to the convened in 2008 and 2012 by The Infectious Diseases Sec- Tunderstanding, diagnosis, and treatment of Cytomega- tion of The Transplantation Society to develop consensus lovirus (CMV).
    [Show full text]
  • Appendices: V Ervolgonderzoek Medicatieveiligheid
    APPENDICES: V ERVOLGONDERZOEK MEDICATIEVEILIGHEID Dit is een bijlage bij het rapport Vervolgonderzoek Medicatieveiligheid en is opgesteld voor het Ministerie van VWS vanuit een samenwerkingsverband tussen het Erasmus MC (Rotterdam), NIVEL (Utrecht), Radboud UMC (Nijmegen) en PHARMO (Utrecht) Januari 2017 Versie 1.0 1 Appendices Hoofstuk 2: Onderzoek naar de mate van opvolging van HARM-Wrestling aanbevelingen (2009-2014) 2 Appendix 1 Appendix 1: Technische omzetting van HARM-Wrestling aanbevelingen naar indicatoren Algemene specificaties Tabel A1a. Bepaling van medicatiegebruik. Geneesmiddel of ATC-code geneesmiddelen groep Antidepressiva N06A Laag gedoseerd ASA B01AC06, B01AC08, B01AC30, N02BA15 (dosering 100mg) of N02BA01 (dosering 80mg) Benzodiazepinen N05CF, N05CD, N05BA of N05CC Beta-blokkers C07 Bisfosfonaten M05BA, M05BB, of M05XX Calcineurine remmers L04AA05 of L04AD01 Carbamazepine N03AF01 Corticosteroiden H02AB Co-trimoxazol J01EE01 Coxibs M01AH Diabetesmedicatie A10 Digoxine C01AA05 Glibenclamide A10BB01 of A10BD02 of A10BD04 H2RA A02BA Itraconazol J02AC02 Kaliumsparende diuretica C03DA, C03DB, of C03EA Kaliumverliezende diuretica C03A, C03B, C03E, C07B, C07CB03, C09BA, C09DA, C09XA52, C03C of C09DX01 Ketoconazol J02AB02 Niet-selectieve NSAID’s N02BA01, N02BA15, N02BA11, N02BA51, N02BA65 of M01A met uitzondering van M01AH, M01AX05, M01AX12, M01AX21, M01AX24, M01AX25 en M01AX26 Laxantia A06A, A02AA02, A02AA03, A02AA04, A06AC, A06AA, of A06AG Lisdiuretica C03C Macroliden J01FA of A02BD04 VKA B01AA Opioïden N02AA met uitzondering van N02AA55, N02AA59 en N02AA79, N02AB, N02AC, N02AD, N02AG, N02AE of N07BC01 Pentamidine P01CX01 PPI’s A02BC of M01AE52 RAS-remmers C09 Sotalol C07AA07 Spironolacton C03DA01 SSRI's N06AB, N06AX21 of N06AX16 Sulonylureumderivaten A10BB, A10BD02 of A10BD04 Thiazidediuretica C03A, C03B, C03EA, C07B, C09BA, C09DA, C09XA52, C09DX01 of C07CB03 TAR B01AC04, B01AC06, B01AC08, B01AC22, B01AC30, N02BA15 (dosering 100mg) of N02BA01 (dosering 80mg) Thienopyridine derivaten B01AC04, B01AC22 of B01AC30 3 Appendix 1 Tabel A1b.
    [Show full text]
  • Surveillance of Antimicrobial Consumption in Europe 2013-2014 SURVEILLANCE REPORT
    SURVEILLANCE REPORT SURVEILLANCE REPORT Surveillance of antimicrobial consumption in Europe in Europe consumption of antimicrobial Surveillance Surveillance of antimicrobial consumption in Europe 2013-2014 2012 www.ecdc.europa.eu ECDC SURVEILLANCE REPORT Surveillance of antimicrobial consumption in Europe 2013–2014 This report of the European Centre for Disease Prevention and Control (ECDC) was coordinated by Klaus Weist. Contributing authors Klaus Weist, Arno Muller, Ana Hoxha, Vera Vlahović-Palčevski, Christelle Elias, Dominique Monnet and Ole Heuer. Data analysis: Klaus Weist, Arno Muller and Ana Hoxha. Acknowledgements The authors would like to thank the ESAC-Net Disease Network Coordination Committee members (Marcel Bruch, Philippe Cavalié, Herman Goossens, Jenny Hellman, Susan Hopkins, Stephanie Natsch, Anna Olczak-Pienkowska, Ajay Oza, Arjana Tambić Andrasevic, Peter Zarb) and observers (Jane Robertson, Arno Muller, Mike Sharland, Theo Verheij) for providing valuable comments and scientific advice during the production of the report. All ESAC-Net participants and National Coordinators are acknowledged for providing data and valuable comments on this report. The authors also acknowledge Gaetan Guyodo, Catalin Albu and Anna Renau-Rosell for managing the data and providing technical support to the participating countries. Suggested citation: European Centre for Disease Prevention and Control. Surveillance of antimicrobial consumption in Europe, 2013‒2014. Stockholm: ECDC; 2018. Stockholm, May 2018 ISBN 978-92-9498-187-5 ISSN 2315-0955
    [Show full text]
  • JULY 2019 Mrx Pipeline a View Into Upcoming Specialty and Traditional Drugs TABLE of CONTENTS
    JULY 2019 MRx Pipeline A view into upcoming specialty and traditional drugs TABLE OF CONTENTS EDITORIAL STAFF Introduction Maryam Tabatabai, PharmD Editor in Chief Senior Director, Drug Information Pipeline Deep Dive Carole Kerzic, RPh Executive Editor Drug Information Pharmacist Keep on Your Radar Consultant Panel Michelle Booth, Pharm D Director, Medical Pharmacy Strategy Becky Borgert, PharmD, BCOP Pipeline Drug List Director, Clinical Oncology Product Development Lara Frick, PharmD, BCPS, BCPP Drug Information Pharmacist Glossary Robert Greer, RPh, BCOP Senior Director, Clinical Strategy and Programs YuQian Liu, PharmD Manager, Specialty Clinical Programs Troy Phelps Senior Director, Analytics Nothing herein is or shall be construed as a promise or representation regarding past or future events and Magellan Rx Management expressly disclaims any and all liability relating to the use of or reliance on the information contained in this presentation. The information contained in this publication is intended for educational purposes only and should not be considered clinical, financial, or legal advice. By receipt of this publication, each recipient agrees that the information contained herein will be kept confidential and that the information will not be photocopied, reproduced, distributed to, or disclosed to others at any time without the prior written consent of Magellan Rx Management. 1 | magellanrx.com INTRODUCTION Welcome to the MRx Pipeline. In its third year of publication, this quarterly report offers clinical insights and competitive intelligence on anticipated drugs in development. Our universal forecast addresses trends applicable across market segments. Traditional and specialty drugs, agents under the pharmacy and medical benefits, new molecular entities, pertinent new and expanded indications for existing medications, and biosimilars are profiled in the report.
    [Show full text]
  • 7. Post-Transplant Infection Considerations
    7. Post-transplant infectious disease considerations Table of Contents 7.1 Viral 7.1.1 Cytomegalovirus 7.1.2 Epstein-Barr Virus and lymphoproliferative disorder 7.1.3 Herpes Simplex and Varicella-Zoster virus 7.1.4 Adenovirus infection 7.1.5 HBV prophylaxis and treatment 7.1.6 HCV prophylaxis and treatment 7.1.7 Arenavirus and West Nile Virus 7.1.8 BK Polyomavirus 7.1.9 Human Parvovirus 7.1.10 RNA Respiratory Viruses 7.2.11 Measles 7.2 Bacterial 7.2.1 Central venous catheter infections and treatment options 7.2.2 Mycobacterium tuberculosis 7.2.3 Non-tuberculosis mycobacterium 7.2.4 Nocardia 7.3 Fungal 7.3.1 PJP 7.3.2 Aspergillus 7.3.3 Cryptococcus 7.3.4 Invasive Candidiasis 7.3.5 Histoplasmosis 7.4 Other 7.4.1 Timing of post-transplant infections 7.4.2 Infectious exposure management 7.4.2.1 Measles 7.4.2.2 Varicella 7.4.2.3 Influenza 7.4.2.4 Tuberculosis 7.4.2.5 Bacterial Meningitis 7.4.3 Immunizations 7.4.4 Toxoplasmosis prophylaxis and treatment 7.1 Viral 7.1.1 Cytomegalovirus Singh N, et al (2020). Effect of Preemptive Therapy vs Antiviral Prophylaxis on Cytomegalovirus Disease in Seronegative Liver Transplant Recipients with Seropositive Donors. JAMA; 323(14):1378-1387. Retrieved from: https://jamanetwork.com/journals/jama/article-abstract/2764457 • Randomized clinical trial comparing the incidence of CMV disease in those high risk CMV liver transplant recipients who received preemptive therapy with valganciclovir 900mg twice daily to antiviral prophylaxis with valganciclovir 900mg daily.
    [Show full text]
  • 13-400 Phrma Stateclinicaltrials MN 120913.Indd
    Research in Your Backyard Developing Cures, Creating Jobs PHARMACEUTICAL CLINICAL TRIALS IN Dots show locations of clinical trials in the state. MINNESOTA Executive Summary Clinical Trials in Minnesota “ Advancements in medicine would not be • Biopharmaceutical research companies have possible without individuals willing to volunteer conducted more than 2,900 clinical trials of new their time to participate in clinical studies. medicines since 1999 in collaboration with the The Minnesota Clinical Research Association state’s local research institutions, including the Clinical Research Institute in Minneapolis and (MCRA) is a collaboration of Minnesota based Plymouth, Twin Cities Clinical Research/ research institutions and professionals who are Prism Clinical Research in Brooklyn Center, committed to objectively informing the general Prism Clinical Research in St. Paul, MAPS public to the benefits and risks involved in Applied Research Center in Edina, Minnesota clinical research far beyond international and Diet Research Center/Frestedt Inc. in St. Louis domestic regulations. MCRA members believe Park, Mercy Hospital in Coon Rapids, St. Mary’s that a fully informed participant is critical to Duluth Clinic in Duluth, St. Cloud Hospital in successful clinical research outcomes.” St. Cloud, St. Paul’s Heart Clinic in St. Paul, the — Jeff Cosgrove, President University of Minnesota School of Medicine in Prism Clinical Research Minneapolis and the Mayo Clinic in Rochester. • The trials have been aimed at a wide array of diseases and medical conditions, ranging from • MCRA provides important clinical research the most debilitating chronic diseases, including education at a time when it is a challenge for cancer, pain, heart disease, obesity and diabetes, to biopharmaceutical and device companies and bothersome allergies, sinusitis, chronic obstructive local research collaborators to recruit volunteers, pulmonary disease (COPD), migraine headaches, and patients often don’t know about trials of pneumonia and rare diseases affecting small new drugs.
    [Show full text]
  • Drug Pipeline Monthly Update June 2021
    Drug Pipeline MONTHLY UPDATE Critical updates in an ever changing environment June 2021 NEW DRUG INFORMATION ™ ● Myfembree (relugolix 40mg, estradiol 1mg, and norethindrone acetate 0.5mg): The U.S. Food and Drug Administration (FDA) has approved Pfizer’s Myfembree (relugolix 40mg, estradiol 1mg, and norethindrone acetate 0.5mg), as a once-daily treatment for the management of heavy menstrual bleeding associated with uterine fibroids in premenopausal women, with a treatment duration of up to 24 months. Uterine fibroids are the most common benign tumors in women of reproductive age and are estimated to affect 20 to 60% of women by the time they reach menopause. The approval of Myfembree is supported by efficacy and safety data from two Phase 3 clinical trials, LIBERTY 1 and LIBERTY 2 which demonstrated a 72.1% and 71.2% response rate respectively in menstrual blood loss at week 24. Additionally, the combination therapy preserved bone mass density in the women enrolled in the clinical trials. Myfembree has launched with a wholesale acquisition cost (WAC) of $974.54 for a 28-day supply.1 ™ ● Lybalvi (olanzapine and samidorphan): The FDA has approved Alkermes’ Lybalvi for the treatment of adults with schizophrenia and for the treatment of adults with bipolar I disorder, as a maintenance monotherapy or for the acute treatment of manic or mixed episodes, as monotherapy or an adjunct to lithium or valproate. Lybalvi is a once-daily, oral atypical antipsychotic composed of olanzapine, an established antipsychotic agent, and samidorphan, a new chemical entity that is designed to mitigate weight gain associated with olanzapine.
    [Show full text]
  • Human Papillomavirus 16 E7 Inactivator of Retinoblastoma Family Proteins Complements Human Cytomegalovirus Lacking UL97 Protein Kinase
    Human papillomavirus 16 E7 inactivator of retinoblastoma family proteins complements human cytomegalovirus lacking UL97 protein kinase Jeremy P. Kamila,1, Adam J. Humeb, Igor Juraka, Karl Mu¨ ngerc, Robert F. Kalejtab, and Donald M. Coena,1 aDepartment of Biological Chemistry and Molecular Pharmacology, and cInfectious Diseases Division, Brigham and Women’s Hospital and Department of Medicine, Harvard Medical School, Boston, MA 02115; and bInstitute for Molecular Virology and McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI 53706 Edited by Ed Harlow, Harvard Medical School, Boston, MA, and approved August 10, 2009 (received for review February 10, 2009) Several different families of DNA viruses encode proteins that individuals [reviewed in (9)]. Nonetheless, HCMV is a leading inactivate the cellular retinoblastoma tumor suppressor protein viral cause of birth defects and life threatening disease in (pRb), which normally functions to bind E2F transcription factors immunocompromised patients, and UL97 is an important target and restrict expression of genes necessary for cellular processes for drugs to ameliorate HCMV disease (10–14). including DNA replication. Human cytomegalovirus (HCMV) UL97, HCMV mutants lacking UL97 produce approximately 10 to a protein kinase functionally orthologous to cellular cyclin-depen- 1,000 fold fewer infectious particles than wild-type virus during dent kinases, phosphorylates pRb on inactivating residues during replication in cultured cells (7, 15–18). Specific defects of these HCMV infection. To assess if such phosphorylation is biologically mutants during viral replication include reduced viral DNA relevant, we tested whether the human papillomavirus type 16 E7 synthesis, impaired exit of capsids from the nucleus (nuclear protein, which inactivates pRb family proteins by direct binding egress), and altered intracellular localization of virion compo- and destabilization, could substitute for UL97 during HCMV infec- nents; pharmacological inhibition of UL97 results in similar tion.
    [Show full text]