Discovery and Early Development of AVI-7537 and AVI-7288 for the Treatment of Ebola Virus and Marburg Virus Infections

被引：85
作者：
Iversen, Patrick L. [1 ]
Warren, Travis K. [2 ]
Wells, Jay B. [2 ]
Garza, Nicole L. [2 ]
Mourich, Dan V. [1 ]
Welch, Lisa S. [2 ]
Panchal, Rekha G. [2 ]
Bavari, Sina [2 ]
机构：
[1] Sarepta Therapeut, Bothell, WA 98021 USA
[2] USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA
来源：
VIRUSES-BASEL | 2012年 / 4卷 / 11期
关键词：
Ebola; Marburg; Phosphorodiamidate Morpholino Oligomer; PMOplus; Therapeutic; Antiviral; PHOSPHORODIAMIDATE MORPHOLINO OLIGOMERS; ENTERICA SEROVAR TYPHIMURIUM; CELL-PENETRATING PEPTIDES; AMINO-ACID-COMPOSITION; ESCHERICHIA-COLI; ANTISENSE OLIGOMERS; NONHUMAN-PRIMATES; TISSUE-CULTURE; C-MYC; INHIBITION;
D O I：
10.3390/v4112806
中图分类号：
Q93 [微生物学];
学科分类号：
071005 ; 100705 ;
摘要：
There are no currently approved treatments for filovirus infections. In this study we report the discovery process which led to the development of antisense Phosphorodiamidate Morpholino Oligomers (PMOs) AVI-6002 (composed of AVI-7357 and AVI-7539) and AVI-6003 (composed of AVI-7287 and AVI-7288) targeting Ebola virus and Marburg virus respectively. The discovery process involved identification of optimal transcript binding sites for PMO based RNA-therapeutics followed by screening for effective viral gene target in mouse and guinea pig models utilizing adapted viral isolates. An evolution of chemical modifications were tested, beginning with simple Phosphorodiamidate Morpholino Oligomers (PMO) transitioning to cell penetrating peptide conjugated PMOs (PPMO) and ending with PMOplus containing a limited number of positively charged linkages in the PMO structure. The initial lead compounds were combinations of two agents targeting separate genes. In the final analysis, a single agent for treatment of each virus was selected, AVI-7537 targeting the VP24 gene of Ebola virus and AVI-7288 targeting NP of Marburg virus, and are now progressing into late stage clinical development as the optimal therapeutic candidates.
引用
收藏
页码：2806 / 2830
页数：25
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