DOCSLIB.ORG

Tesi Definitiva DMST Elisa Rita Ceresola

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Tesi Definitiva DMST Elisa Rita Ceresola CHARACTERIZATION OF NEW SYNTHETIC OR NATURAL COMPOUNDS WITH BROAD SPECTRUM OR DUAL ANTIVIRAL ACTIVITY IN HIV-1 TREATMENT PhD Degree Program in Experimental and Translational Medicine UNIVERSITY OF INSUBRIA Ph.D. Candidate: Elisa Rita Ceresola Supervisor: Prof. Filippo Canducci Academic year 2017-2018 Alla Luce che guida i miei passi, ai sorrisi innocenti che danno gioia alla mia vita 2 SUMMARY 1 INTRODUCTION ................................................................................................................6 1.1 CURRENTLY AVAILABLE DRUGS FOR HIV-1 TREATMENT ...........................6 1.2 HIV INTEGRASE ...................................................................................................... 10 1.2.1 MECHANISM OF VIRAL INTEGRATION ........................................................ 10 1.2.2 STRUCTURE OF HIV INTEGRASE ................................................................... 12 1.2.3 HIV INTEGRASE INIBITHORS (INI) ................................................................. 13 1.2.3.1 Integrase Strand Transfer Inhibitors (INSTIs) .................................................... 14 1.2.3.2 Allosteric Integrase Inhibitors (ALLINIs) .......................................................... 17 1.2.3.3 Dual inhibitors .................................................................................................. 20 1.3 HIV-1 MICROBICIDES ............................................................................................ 23 1.3.1 THE ENTRY PROCESS....................................................................................... 23 1.3.1.1 HIV-1 Entry Process ......................................................................................... 23 1.3.1.2 The relationship between HIV-1 and HSV-2...................................................... 25 1.3.1.3 HSV-2 entry process ......................................................................................... 28 1.3.2 TOPICAL MICROBICIDES ................................................................................. 29 1.3.2.1 Past, present and future of anti-HIV-1 and HSV-2 microbicides ........................ 31 1.3.2.2 The delivery system .......................................................................................... 35 1.4 AIM OF THE WORK ................................................................................................ 38 2 MATERIAL AND METHODS .......................................................................................... 40 2.1 MATERIALS AND METHODS (PART I) ................................................................ 40 2.1.1 BIOCHEMICAL STUDIES .................................................................................. 40 2.1.1.1 Preparation of recombinant proteins .................................................................. 40 2.1.1.2 HTRF LEDGF-dependent and -independent assay ............................................. 40 2.1.1.3 HTRF-based integrase-LEDGF interaction assay ............................................... 41 2.1.1.4 HTRF-based IN subunit exchange assay ............................................................ 41 2.1.1.5 RT Protein expression and purification .............................................................. 42 2.1.1.6 RNase H polymerase-independent cleavage assay ............................................. 42 2.1.1.7 DNA polymerase assay ..................................................................................... 42 2.1.2 CELLULAR BASED EXPERIMENT................................................................... 43 2.1.2.1 Cell-based assays .............................................................................................. 43 2.1.2.2 Time-of-addition assay (TOA) .......................................................................... 43 2.2 MATERIALS AND METHODS (PART II) .............................................................. 45 3 2.2.1 CHEMISTRY ....................................................................................................... 45 2.2.2 ANTIVIRAL ACTIVITY AND CELL TOXICITY ............................................... 48 2.2.2.1 Molecular cloning ............................................................................................. 48 2.2.2.2 Phenotypic analyses with fully replicating recombinant HIV-1 strains and clonal viral variants selected in patients failing integrase inhibitors on TZM-bl cells and human CD4+ lymphocyte ............................................................................................................ 49 2.2.2.3 HSV-1 and HSV-2 antiviral activity in Vero Cells ............................................. 50 2.2.2.4 Vero Cell viability ............................................................................................. 51 2.2.2.5 Human papilloma pseudovirus (HPV16 PsV) production ................................... 51 2.2.2.6 HPV-16 inhibition assay in HeLa cells .............................................................. 52 2.2.2.7 Inhibition of antiviral activity by fetal bovine serum .......................................... 52 2.2.2.8 Inhibition of antiviral activity by purified bovine serum albumin ....................... 53 2.2.2.9 Antiviral activity of compound 2 in a gel formulation ........................................ 53 2.2.2.10 Time of addition assay on compound 2 .......................................................... 54 2.2.3 ADME ASSAY .................................................................................................... 54 2.2.3.1 Chemicals and Excipients .................................................................................. 54 2.2.3.2 UV/HPLC-MS method ...................................................................................... 54 2.2.3.3 Aqueous Solubility ............................................................................................ 55 2.2.3.4 Parallel Artificial Membrane Permeability Assay (PAMPA) .............................. 55 2.2.3.5 Metabolic Stability in HLM (Human Liver Microsomes) ................................... 56 2.2.3.6 Solubility assessment ........................................................................................ 56 2.2.3.7 Gel formulation ................................................................................................. 57 2.2.3.8 Storage Stability and rheological characterization .............................................. 57 2.2.3.9 Binding Fluorimetric Assay ............................................................................... 57 3 RESULTS ........................................................................................................................... 59 3.1 RESULTS (PART I) ................................................................................................... 59 3.1.1 HOMOGENEOUS TIME-RESOLVED FLUORESCENCE (HTRF) ASSAYS ..... 59 3.1.2 CELL-BASED HIV REPLICATION ASSAY....................................................... 61 3.1.2.1 Cell based assay on fully replicating HIV-1 laboratory strain ............................. 61 3.1.2.2 Cell based assay on INSTI-resistant mutants...................................................... 61 3.1.2.3 TOA experiment ............................................................................................... 62 3.1.3 BIOCHEMICAL ASSAYS ON RT FUNCTIONS ................................................ 63 3.2 RESULTS (PART II).................................................................................................. 65 3.2.1 ANTIVIRAL ACTIVITIES OF RHODANINE DERIVATIVES ........................... 65 3.2.1.1 Antiviral activity and cytotoxicity on TZM-bl cell line infected with HIV-1 laboratory strains .............................................................................................................. 65 3.2.1.2 Antiviral activity and cytotoxicity on human CD4+ lymphocytes ....................... 67 4 3.2.1.3 Antiviral activity and cytotoxicity on Vero cell line infected with HSV-2 laboratory strain and HeLa infected with HPV-16 PsVs .................................................... 68 3.2.1.4 Binding to Fetal Bovine Serum.......................................................................... 70 3.2.1.5 Binding to Bovine purified serum Albumin ....................................................... 71 3.2.1.6 Antiviral activity of compound 2 in a microbicide gel formulation ..................... 72 3.2.1.7 Time of addition assay on compound 2 .............................................................. 72 3.2.2 IN VITRO ADME STUDIES ................................................................................. 74 3.2.2.1 Solubility, permeability and metabolic stability ................................................. 74 3.2.2.2 Albumin binding fluorimetric assay ................................................................... 74 3.2.2.3 Storage Stability of compound 2 Gel Formulation ............................................. 75 4 DISCUSSION ..................................................................................................................... 76 5 CONCLUSIONS ................................................................................................................ 85 6 REFERENCES ................................................................................................................... 87 7 ACKNOLEDGMENTS ...................................................................................................... 98 5 1 INTRODUCTION 1.1 CURRENTLY
Load more

Recommended publications
  • Annual Conference Online 2021
    CANDIDAANNUAL CONFERENCEAND ONLINECANDIDIASIS 2021 2021 21–27 March 2021 POSTER ABSTRACT BOOK #Candida2021 001A Candida auris gene expression: modulation upon caspofungin treatment Lysangela Alves1, Rafaela Amatuzzi1, Daniel Zamith-Miranda2, Sharon Martins1, Joshua Nosanchuk2 1Carlos Chagas Institute, Curitiba, Brazil. 2Departments of Medicine (Division of Infectious Diseases) and Microbiology and Immunology, Albert Einstein College of Medicine, New York, USA Abstract Candida auris has emerged as a serious worldwide threat by causing invasive infections in humans that are frequently resistant to one or more conventional antifungal medications, resulting in high mortality rates. Against this backdrop, health warnings around the world have focused efforts on understanding C. auris fungal biology and effective treatment approaches to combat this fungus. To date, there is little information about C. auris gene expression regulation in response to antifungal treatment. Our integrated analyses focused on the comparative transcriptomics of C. auris in the presence and absence of caspofungin as well as a detailed analysis of the yeast’s extracellular vesicle (EV)-RNA composition. The results showed that genes coding oxidative stress response, ribosomal proteins, cell wall, and cell cycle were significantly up-regulated in the presence of caspofungin, whereas transcriptional regulators and proteins related to nucleus were down-regulated. The mRNAs in the EVs were associated with the stress responses induced by caspofungin and the ncRNA content of the EVs shifted during caspofungin treatment. Altogether, the results provide further insights into the fungal response to caspofungin and demonstrate that analyses of C. auris growth under antifungal stress can elucidate resistance and survival mechanisms of this fungus in response to medical therapy.
    [Show full text]
  • Glossary Terms
    Glossary Terms € 1584 5W6 5501 a 7181, 12203 5’UTR 8126 a-g Transformation 6938 6Q1 5500 r 7181 6W1 5501 b 7181 a 12202 b-b Transformation 6938 A 12202 d 7181 AAV 10815 Z 1584 Abandoned mines 6646 c 5499 Abiotic factor 148 f 5499 Abiotic 10139, 11375 f,b 5499 Abiotic stress 1, 10732 f,i, 5499 Ablation 2761 m 5499 ABR 1145 th 5499 Abscisic acid 9145 th,Carnot 5499 Absolute humidity 893 th,Otto 5499 Absorbed dose 3022, 4905, 8387, 8448, 8559, 11026 v 5499 Absorber 2349 Ф 12203 Absorber tube 9562 g 5499 Absorption, a(l) 8952 gb 5499 Absorption coefficient 309 abs lmax 5174 Absorption 309, 4774, 10139, 12293 em lmax 5174 Absorptivity or absorptance (a) 9449 μ1, First molecular weight moment 4617 Abstract community 3278 o 12203 Abuse 6098 ’ 5500 AC motor 11523 F 5174 AC 9432 Fem 5174 ACC 6449, 6951 r 12203 Acceleration method 9851 ra,i 5500 Acceptable limit 3515 s 12203 Access time 1854 t 5500 Accessible ecosystem 10796 y 12203 Accident 3515 1Q2 5500 Acclimation 3253, 7229 1W2 5501 Acclimatization 10732 2W3 5501 Accretion 2761 3 Phase boundary 8328 Accumulation 2761 3D Pose estimation 10590 Acetosyringone 2583 3Dpol 8126 Acid deposition 167 3W4 5501 Acid drainage 6665 3’UTR 8126 Acid neutralizing capacity (ANC) 167 4W5 5501 Acid (rock or mine) drainage 6646 12316 Glossary Terms Acidity constant 11912 Adverse effect 3620 Acidophile 6646 Adverse health effect 206 Acoustic power level (LW) 12275 AEM 372 ACPE 8123 AER 1426, 8112 Acquired immunodeficiency syndrome (AIDS) 4997, Aerobic 10139 11129 Aerodynamic diameter 167, 206 ACS 4957 Aerodynamic
    [Show full text]
  • The Design, Synthesis and Optimization of Allosteric Hiv-1
    THE DESIGN, SYNTHESIS AND OPTIMIZATION OF ALLOSTERIC HIV-1 INTEGRASE INHIBITORS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Janet Antwi Graduate Program in Pharmaceutical Sciences The Ohio State University 2017 Dissertation Committee: Professor James R. Fuchs, Advisor Professor Werner Tjarks Professor Karl A. Werbovetz Copyright by Janet Antwi 2017 Abstract In the past quarter century, there has been tremendous progress in the discovery of antiretroviral therapy, making HIV/AIDS a manageable chronic disease. However, the HIV virus is relentless and continues to evolve under drug pressure to escape control and continue infection. The enzyme HIV integrase is responsible for the incorporation of viral double stranded DNA into a host chromosomal DNA and has recently become an attractive target in combating HIV resistance. Raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG) are three clinically approved active-site integrase inhibitors. Unfortunately, mutations of the enzyme observed in patients have resulted in resistance to thedrug in the clinic. A new approach to targeting integrase (IN) is the development of allosteric inhibitors that specifically target the protein-protein interaction between IN and its cellular cofactor LEDGF/p75. Recently discovered quinoline-based allosteric integrase inhibitor (ALLINI) B1224436 was the first compound to advance into clinical trials but was discontinued due to poor pharmacokinetic properties including low in vivo clearance. In addition, several reports have revealed the emergence of resistance due to mutation to quinoline based ALLINIs. Applying scaffold hopping approach, several pyridine-based, thiophenes, ii pyrazoles, isoquinolines and other heteroaromatic cores have been studied as ALLINIs.
    [Show full text]
  • Potential Drug Candidates Underway Several Registered Clinical Trials for Battling COVID-19
    Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 20 April 2020 doi:10.20944/preprints202004.0367.v1 Potential Drug Candidates Underway Several Registered Clinical Trials for Battling COVID-19 Fahmida Begum Minaa, Md. Siddikur Rahman¥a, Sabuj Das¥a, Sumon Karmakarb, Mutasim Billahc* aDepartment of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi-6205, Bangladesh bMolecular Biology and Protein Science Laboratory, University of Rajshahi, Rajshahi-6205, Bangladesh cProfessor Joarder DNA & Chromosome Research Laboratory, University of Rajshahi, Rajshahi-6205, Bangladesh *Corresponding Author: Mutasim Billah, Professor Joarder DNA & Chromosome Research Laboratory, University of Rajshahi, Rajshahi, Bangladesh Corresponding Author Mail: [email protected] ¥Co-second author Abstract The emergence of new type of viral pneumonia cases in China, on December 31, 2019; identified as the cause of human coronavirus, labeled as "COVID-19," took a heavy toll of death and reported cases of infected people all over the world, with the potential to spread widely and rapidly, achieved worldwide prominence but arose without the procurement guidance. There is an immediate need for active intervention and fast drug discovery against the 2019-nCoV outbreak. Herein, the study provides numerous candidates of drugs (either alone or integrated with another drugs) which could prove to be effective against 2019- nCoV, are under different stages of clinical trials. This review will offer rapid identification of a number of repurposable drugs and potential drug combinations targeting 2019-nCoV and preferentially allow the international research community to evaluate the findings, to validate the efficacy of the proposed drugs in prospective trials and to lead potential clinical practices. Keywords: COVID-19; Drugs; 2019-nCoV; Clinical trials; SARS-CoV-2 Introduction A new type of viral pneumonia cases occurred in Wuhan, Hubei Province in China, on December 31, 2019; named "COVID-19" on January 12, 2020 by the World Health Organization (WHO) [1].
    [Show full text]
  • 2019 Annual Report
    2019 Annual Report 1 TABLE OF CONTENTS - 2 DEPARTMENT PHOTO - 3 MISSION - 4 PRIMARY FACULTY PROMOTIONS & DEPARTURES - 5 NEW APPOINTMENTS OF SECONDARY FACULTY-6 SECONDARY FACULTY DEPARTURES – 8 IN MEMORIAM – 9 FACULTY WITH PRIMARY APPOINTMENTS - 10 FACULTY WITH SECONDARY APPOINTMENTS - 21 FACULTY WITH EMERITUS APPOINTMENTS – 31 FACULTY WITH ADJUNCT APPOINTMENTS - 32 ADMINISTRATIVE STAFF - 32 NEW GRADUATE STUDENT CLASS – 33 GRADUATE STUDENTS – 36 GRADUATES– 37 FACULTY HONORS – 39 STUDENT HONORS - 40 PUBLICATIONS - 42 ABSTRACTS - 47 RESEARCH GRANTS ACTIVE - 59 RESEARCH GRANTS SUBMITTED - 68 INVITED SCIENTIFIC PRESENTATIONS - 76 INTELLECTUAL PROPERTY ACTIONS – 80 DEPARTMENTAL COURSES - 81 STANDING COMMITTEES – 82 NCI CANCER EDUCATION PROGRAM - 83 2 3 MISSION The Department of Pharmacology and Toxicology will ensure academic excellence and achievement of regional, national, and international recognition for the quality of its educational, research, and service activities. Guided by the University of Louisville and the School of Medicine Strategic Plans, the mission of the Department of Pharmacology and Toxicology focuses on five broad objectives: • Provide instruction in pharmacology and toxicology of the highest quality for the education and preparation of medical, dental, and other health care professional students. Emphasis is placed on the fundamental principles necessary for life-long learning and the essential knowledge required for rational, effective, and safe use of drug therapy. • Advance biomedical knowledge through high quality research and other scholarly activities, particularly in pharmacology and toxicology and other areas of focus within the University of Louisville and School of Medicine Strategic Plans. • Provide robust research and educational experiences in pharmacology and toxicology for the education and training of future biomedical scientists who will provide and advance biomedical education, research, and service.
    [Show full text]
  • Updates in Hiv Therapeutics and Prevention
    5/17/2018 UPDATES IN HIV THERAPEUTICS AND PREVENTION Sean Kelly, MD Vanderbilt Division of Infectious Diseases May 17, 2018 Agenda • New Agents, Old Classes • Novel Therapies • Updates on long-acting ART • Updates on dual therapy • Updates on adverse events • Prevention/Pre-Exposure Prophylaxis This just in! • Bictegravir/tenofovir alafenamide/emtricitabine • Dolutegravir/rilpivirine • Ibalizumab 1 5/17/2018 New HIV drugs (from existing classes) Doravirine • NNRTI with fewer CNS adverse effects than EFV • Can be used in the setting of the most common NNRTI resistance mutations (K103N, Y181C, G190A) • DRIVE – phase III study • 766 participants randomized to 2 NRTIs + doravirine vs. 2 NRTIs + DVR/r • Doravirine was non-inferior to DRV/r at 48 weeks • Doravirine yielded a more favorable lipid profile than DRV/r Molina JM et al. (Squires K presenting) Doravirine is non-inferior to darunavir/r in phase 3 treatment- naive trial at week 48. Conference on Retroviruses and Opportunistic Infections (CROI 2017), Seattle, abstract 45LB 2017 Doravirine • DRIVE-AHEAD • Phase III study evaluating DOR/TDF/3TC vs TDF/FTC/EFV (Atripla®) in ART-naïve participants • DOR-regimen was non-inferior at 48 weeks • Fewer neuropsychiatric adverse events with DOR-regimen • DRIVE-SHIFT • Phase III study evaluating switch from boosted PI-based regimen to DOR/TDF/3TC • Results pending Squires KE, Molina JM, Sax PE, et al. Fixed dose combination of doravirine/lamivudine/TDF is non-inferior to efavirenz/emtricitabine/TDF in treatment-naïve adults with HIV-1 infection: week 48 results of the Phase 3 DRIVE-AHEAD study. 9th IAS Conference on HIV Science (IAS 2017), July 23- 26, 2017, Paris.
    [Show full text]
  • Mutational Studies of Novel Screened Molecules Against Wild and Mutated HIV-1 Integrase Using Molecular Docking Studies Pawan Gupta1,2*, Prabha Garg2
    Research Article Mutational studies of novel screened molecules against wild and mutated HIV-1 integrase using molecular docking studies Pawan Gupta1,2*, Prabha Garg2 ABSTRACT Background and Aim: The screened molecules which proposed novel HIV-1 integrase inhibitors were collected from the literature. Mutational studies were performed to check whether these molecules are having good binding affinity against mutated HIV-1 IN or not using molecular docking technique. Materials and Methods: First, homology models of the mutated HIV-1 IN were prepared and subsequently all the models were refined and optimized in MODELLER program. Next, molecular docking studies were performed into the active site of mutated HIV-1 IN models using the proposed inhibitors in AutoDock 4.1 program. The results of these studies were compared with the wild type docking studies. Results: The docking studies were found that some of the screened molecules (ZINC1245110, 131614, 92749, ZINC05181828, and ZINC13147504) followed the same binding patterns (in term of locations, interactions, and binding score) as found with wild type HIV-1 IN. Conclusions: Computationally, the same binding patterns were exhibited by these molecules (ZINC1245110, 131614, 92749, ZINC05181828, and ZINC13147504) against mutated models as wild type. This elucidated that these molecules having susceptibility against the drug-resistant HIV-1 IN. Hence, these molecules may be used as a starting point to design novel inhibitors against mutated HIV-1 IN, which need to be confirmed experimentally. KEY WORDS: Docking, Drug resistance, Homology modeling, HIV-1 integrase, Mutation INTRODUCTION Drug resistance is the inevitable consequence of incomplete suppression of HIV-1 replication. The Human immuno-virus (HIV) causes AIDS.
    [Show full text]
  • Viribus Unitis: Drug Combinations As a Treatment Against COVID-19
    Viribus Unitis: Drug Combinations as a Treatment against COVID-19 Eugene N. Muratova,* and Alexey Zakharovb a Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA. b National Center for Advancing Translational Sciences (NCATS), 9800 Medical Center Drive, Rockville, Mar land 20850, United States Corresponding Authors * Address for correspondence: 301 Beard Hall, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA; Telephone: (919) 966-3459; FAX: (919) 966- 0204; E-mail: [email protected] Abstract The opportunities that may be provided by synergistic antiviral action of drugs for battling SARS-CoV2 are currently underestimated. Modern AI technologies realized as text, data, and knowledge mining and analytics tools provide the researchers with unprecedented opportunities for “smart” design of drug combinations with synergistic antiviral activities. The goal of this study is to emphasize the combination therapy as a potential treatment against COVID-19 and to utilize the combination of modern machine learning and AI technologies with our expertise to select the most promising drug combinations with further experimental validation. To the best of our knowledge, we are the first who applied the combination of data, text, and knowledge mining and modeling towards identification of drug combinations against SARS-CoV2. As a result, we have identified 281 combinations of 38 drugs that may serve as potential treatment for COVID-19. Among them, we selected twenty binary combinations that were submitted to experimental testing and twenty treble drug combinations that will be submitted for experimental testing as soon as necessary infrastructure will be developed.
    [Show full text]
  • Anti-Viral Griffithsin Compounds, Compositions, and Methods of Use
    (19) & (11) EP 2 314 349 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 27.04.2011 Bulletin 2011/17 A61P 31/12 (2006.01) A61K 38/16 (2006.01) A61K 39/42 (2006.01) (21) Application number: 10014895.6 (22) Date of filing: 01.12.2006 (84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • O’Keefe, Barry R. HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI Frederick , MD 21702 (US) SK TR • Mori, Toshiyuki Designated Extension States: San Francisco, CA 94158 (US) AL BA HR MK RS • McMahon, James B. Frederick, MD 21701 (US) (30) Priority: 01.12.2005 US 741403 P (74) Representative: Grünecker, Kinkeldey, (62) Document number(s) of the earlier application(s) in Stockmair & Schwanhäusser accordance with Art. 76 EPC: Anwaltssozietät 06838737.2 / 1 976 596 Leopoldstrasse 4 80802 München (DE) (71) Applicant: The Government of the United States of America, as Remarks: represented by the Secretary, Department of This application was filed on 23-11-2010 as a Health and Human Services divisional application to the application mentioned Rockville, MD 20852 (US) under INID code 62. (54) Anti-viral griffithsin compounds, compositions, and methods of use (57) A method of inhibiting a viral infection of a host or an antibody to the anti-viral polypeptide. A method of comprising administering to the host an anti-viral grif- inhibiting a virus in a sample comprising contacting the fithsin polypeptide comprising SEQ ID NO: 3 or a frag- sample with an anti-viral griffithsin polypeptide or anti- ment thereof comprising at least eight contiguous amino body thereto also is provided.
    [Show full text]
  • Strategies for Targeting SARS Cov-2: Small Molecule Inhibitors—The Current Status
    REVIEW published: 18 September 2020 doi: 10.3389/fimmu.2020.552925 Strategies for Targeting SARS CoV-2: Small Molecule Inhibitors—The Current Status Narasimha M. Beeraka 1†, Surya P. Sadhu 2†, SubbaRao V. Madhunapantula 1,3*, Rajeswara Rao Pragada 2, Andrey A. Svistunov 4, Vladimir N. Nikolenko 4,5, Liudmila M. Mikhaleva 6 and Gjumrakch Aliev 6,7,8,9* 1 Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), JSS Academy of Higher Education & Research (JSS AHER), Mysore, India, 2 AU College of Pharmaceutical Sciences, Andhra University, Visakhapatnam, India, 3 Special Interest Group in Cancer Biology and Cancer Stem Cells (SIG-CBCSC), JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysore, India, 4 I. M. Sechenov First Moscow State Edited by: Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia, 5 Department Denise L. Doolan, of Normal and Topographic Anatomy, M.V. Lomonosov Moscow State University, Moscow, Russia, 6 Research Institute of James Cook University, Australia Human Morphology, Moscow, Russia, 7 Sechenov First Moscow State Medical University (Sechenov University), Moscow, 8 9 Reviewed by: Russia, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Moscow, Russia, GALLY Rong Hai, International Research Institute, San Antonio, TX, United States University of California, Riverside, United States Severe Acute Respiratory Syndrome-Corona Virus-2 (SARS-CoV-2) induced Coronavirus Katie Louise Flanagan, RMIT University, Australia Disease - 19 (COVID-19) cases have been increasing at an alarming rate (7.4 *Correspondence: million positive cases as on June 11 2020), causing high mortality (4,17,956 deaths SubbaRao V.
    [Show full text]
  • Fourth Quarter Product Sales of $2.13 Billion, up 11% Year Over Year
    Gilead Sciences Announces Fourth Quarter and Full Year 2011 Financial Results February 2, 2012 4:06 PM ET - Fourth Quarter Product Sales of $2.13 Billion, up 11% Year over Year - - Full Year 2011 Product Sales of $8.10 Billion, up 10% over 2010 - - Full Year 2011 Non-GAAP EPS of $3.86, up 5% over 2010 - - Full Year 2011 Operating Cash Flows of $3.64 Billion - FOSTER CITY, Calif.--(BUSINESS WIRE)--Feb. 2, 2012-- Gilead Sciences, Inc. (Nasdaq:GILD) announced today its results of operations for the fourth quarter and full year 2011. Total revenues for the fourth quarter of 2011 increased 10 percent to $2.20 billion, from $2.00 billion for the fourth quarter of 2010. Net income for the fourth quarter of 2011 was $665.1 million, or $0.87 per diluted share, compared to $629.4 million, or $0.76 per diluted share for the fourth quarter of 2010. Non-GAAP net income for the fourth quarter of 2011, which excludes after-tax acquisition-related, restructuring and stock-based compensation expenses, was $743.1 million, or $0.97 per diluted share, compared to $779.3 million, or $0.95 per diluted share for the fourth quarter of 2010. Full year 2011 total revenues were $8.39 billion, up 5 percent compared to $7.95 billion for 2010. Net income for 2011 was $2.80 billion, or $3.55 per diluted share, compared to $2.90 billion, or $3.32 per diluted share for 2010. Non-GAAP net income for 2011, which excludes after-tax acquisition-related, restructuring and stock-based compensation expenses, was $3.04 billion, or $3.86 per diluted share, compared to $3.21 billion, or $3.69 per diluted share for 2010.
    [Show full text]
  • Novel Antiretroviral Structures from Marine Organisms
    molecules Review Novel Antiretroviral Structures from Marine Organisms Karlo Wittine , Lara Safti´c,Željka Peršuri´c and Sandra Kraljevi´cPaveli´c* University of Rijeka, Department of Biotechnology, Centre for high-throughput technologies, Radmile Matejˇci´c2, 51000 Rijeka, Croatia * Correspondence: [email protected]; Tel.: +385-51-584-550 Academic Editor: Kyoko Nakagawa-Goto Received: 2 September 2019; Accepted: 19 September 2019; Published: 26 September 2019 Abstract: In spite of significant advancements and success in antiretroviral therapies directed against HIV infection, there is no cure for HIV, which scan persist in a human body in its latent form and become reactivated under favorable conditions. Therefore, novel antiretroviral drugs with different modes of actions are still a major focus for researchers. In particular, novel lead structures are being sought from natural sources. So far, a number of compounds from marine organisms have been identified as promising therapeutics for HIV infection. Therefore, in this paper, we provide an overview of marine natural products that were first identified in the period between 2013 and 2018 that could be potentially used, or further optimized, as novel antiretroviral agents. This pipeline includes the systematization of antiretroviral activities for several categories of marine structures including chitosan and its derivatives, sulfated polysaccharides, lectins, bromotyrosine derivatives, peptides, alkaloids, diterpenes, phlorotannins, and xanthones as well as adjuvants to the HAART therapy such as fish oil. We critically discuss the structures and activities of the most promising new marine anti-HIV compounds. Keywords: antiretroviral agents; anti-HIV; marine metabolites; natural products; drug development 1. Introduction Human immunodeficiency virus (HIV) infections pose a global challenge given that in 2017, according to the World Health Organization data, 36.9 million people were living with HIV and additional 1.8 million people were becoming newly infected globally (Table1) .
    [Show full text]