The paramyxovirus polymerase complex as a target for next-generation anti-paramyxovirus therapeutics

被引:43
作者
Cox, Robert [1 ]
Plemper, Richard K. [1 ]
机构
[1] Georgia State Univ, Petit Sci Ctr, Inst Biomed Sci, Atlanta, GA 30303 USA
关键词
Paramyxovirus; RNA-dependent RNA polymerase; antiviral therapy; nucleoside analogs; allosteric inhibitor; VESICULAR-STOMATITIS-VIRUS; DEPENDENT RNA-POLYMERASE; RESPIRATORY SYNCYTIAL VIRUS; PROTEIN-PROTEIN INTERACTIONS; C-TERMINAL DOMAIN; SMALL-MOLECULE INHIBITORS; HOST-DIRECTED INHIBITORS; MEASLES-VIRUS; SENDAI-VIRUS; MESSENGER-RNA;
D O I
10.3389/fmicb.2015.00459
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The paramyxovirus family includes major human and animal pathogens, including measles virus, mumps virus, and human respiratory syncytial virus (RSV), as well as the emerging zoonotic Hendra and Nipah viruses. In the U.S., RSV is the leading cause of infant hospitalizations due to viral infectious disease. Despite their clinical significance, effective drugs for the improved management of paramyxovirus disease are lacking. The development of novel anti-paramyxovirus therapeutics is therefore urgently needed. Paramyxoviruses contain RNA genomes of negative polarity, necessitating a virus-encoded RNA-dependent RNA polymerase (RdRp) complex for replication and transcription. Since an equivalent enzymatic activity is absent in host cells, the RdRp complex represents an attractive druggable target, although structure-guided drug development campaigns are hampered by the lack of high-resolution RdRp crystal structures. Here, we review the current structural and functional insight into the paramyxovirus polymerase complex in conjunction with an evaluation of the mechanism of activity and developmental status of available experimental RdRp inhibitors. Our assessment spotlights the importance of the RdRp complex as a premier target for therapeutic intervention and examines how high-resolution insight into the organization of the complex will pave the path toward the structure-guided design and optimization of much-needed next-generation paramyxovirus RdRp blockers.
引用
收藏
页数:14
相关论文
共 159 条
[1]   Nonnucleoside Reverse Transcriptase Inhibitor Resistance and the Role of the Second-Generation Agents [J].
Adams, Jessica ;
Patel, Nimish ;
Mankaryous, Nancy ;
Tadros, Mariam ;
Miller, Christopher D. .
ANNALS OF PHARMACOTHERAPY, 2010, 44 (01) :157-165
[2]  
Andrei G, 2008, CURR OPIN INVEST DR, V9, P132
[3]   Small-Molecule Inhibitors of Protein-Protein Interactions: Progressing toward the Reality [J].
Arkin, Michelle R. ;
Tang, Yinyan ;
Wells, James A. .
CHEMISTRY & BIOLOGY, 2014, 21 (09) :1102-1114
[4]   Small-molecule inhibitors of protein-protein interactions: Progressing towards the dream [J].
Arkin, MR ;
Wells, JA .
NATURE REVIEWS DRUG DISCOVERY, 2004, 3 (04) :301-317
[5]   Measles virus infection in rhesus macaques: Altered immune responses and comparison of the virulence of six different virus strains [J].
Auwaerter, PG ;
Rota, PA ;
Elkins, WR ;
Adams, RJ ;
DeLozier, T ;
Shi, YQ ;
Bellini, WJ ;
Murphy, BR ;
Griffin, DE .
JOURNAL OF INFECTIOUS DISEASES, 1999, 180 (04) :950-958
[6]   ENCAPSIDATION OF SENDAI VIRUS GENOME RNAS BY PURIFIED NP PROTEIN DURING INVITRO REPLICATION [J].
BAKER, SC ;
MOYER, SA .
JOURNAL OF VIROLOGY, 1988, 62 (03) :834-838
[7]   The respiratory syncytial virus nucleoprotein-RNA complex forms a left-handed helical nucleocapsid [J].
Bakker, Saskia E. ;
Duquerroy, Stephane ;
Galloux, Marie ;
Loney, Colin ;
Conner, Edward ;
Eleouet, Jean-Francois ;
Rey, Felix A. ;
Bhella, David .
JOURNAL OF GENERAL VIROLOGY, 2013, 94 :1734-1738
[8]   Reverse transcription of the HIV-1 pandemic [J].
Basavapathruni, Aravind ;
Anderson, Karen S. .
FASEB JOURNAL, 2007, 21 (14) :3795-3808
[9]   2P2Idb: a structural database dedicated to orthosteric modulation of protein-protein interactions [J].
Basse, Marie Jeanne ;
Betzi, Stephane ;
Bourgeas, Raphael ;
Bouzidi, Sofia ;
Chetrit, Bernard ;
Hamon, Veronique ;
Morelli, Xavier ;
Roche, Philippe .
NUCLEIC ACIDS RESEARCH, 2013, 41 (D1) :D824-D827
[10]   Conformational flexibility in recombinant measles virus nucleocapsids visualised by cryo-negative stain electron microscopy and real-space helical reconstruction [J].
Bhella, D ;
Ralph, A ;
Yeo, RP .
JOURNAL OF MOLECULAR BIOLOGY, 2004, 340 (02) :319-331