Identification of the ENT1 antagonists dipyridamole and dilazep as amplifiers of oncolytic herpes simplex virus-1 replication.
Oncolytic herpes simplex virus-1 (oHSV) vectors selectively replicate in tumor cells, where they kill through oncolysis while sparing normal cells. One of the drawbacks of oHSV vectors is their limited replication and spread to neighboring cancer cells. Here, we report the outcome of a high-throughput chemical library screen to identify small-molecule compounds that augment the replication of oHSV G47Delta. Of the 2,640-screened bioactives, 6 compounds were identified and subsequently validated for enhanced G47Delta replication. Two of these compounds, dipyridamole and dilazep, interfered with nucleotide metabolism by potently and directly inhibiting the equilibrative nucleoside transporter-1 (ENT1). Replicative amplification promoted by dipyridamole and dilazep were dependent on HSV mutations in ICP6, the large subunit of ribonucleotide reductase. Our results indicate that ENT1 antagonists augment oHSV replication in tumor cells by increasing cellular ribonucleoside activity.
Passer
Brent J
BJ
Departments of Neurosurgery and Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. bpasser@partners.org
Cheema
Tooba
T
Zhou
Bingsen
B
Wakimoto
Hiroaki
H
Zaupa
Cecile
C
Razmjoo
Mani
M
Sarte
Jason
J
Wu
Shulin
S
Wu
Chin-lee
CL
Noah
James W
JW
Li
Qianjun
Q
Buolamwini
John K
JK
Yen
Yun
Y
Rabkin
Samuel D
SD
Martuza
Robert L
RL
D000818:Animals; D020650:Combinatorial Chemistry Techniques; D004109:Dilazep / Q000494:pharmacology*; D004176:Dipyridamole / Q000494:pharmacology*; D033721:Equilibrative Nucleoside Transporter 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020869:Gene Expression Profiling; D006561:Herpes Simplex / Q000378:metabolism / Q000628:therapy / Q000821:virology; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D009924:Organ Culture Techniques; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012264:Ribonucleotide Reductases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects*
D033721:Equilibrative Nucleoside Transporter 1; D012333:RNA, Messenger; D004176:Dipyridamole; D012264:Ribonucleotide Reductases; D004109:Dilazep