Ten years of dengue drug discovery: progress and prospects.
To combat neglected diseases, the Novartis Institute of Tropical Diseases (NITD) was founded in 2002 through private-public funding from Novartis and the Singapore Economic Development Board. One of NITD's missions is to develop antivirals for dengue virus (DENV), the most prevalent mosquito-borne viral pathogen. Neither vaccine nor antiviral is currently available for DENV. Here we review the progress in dengue drug discovery made at NITD as well as the major discoveries made by academia and other companies. Four strategies have been pursued to identify inhibitors of DENV through targeting both viral and host proteins: (i) HTS (high-throughput screening) using virus replication assays; (ii) HTS using viral enzyme assays; (iii) structure-based in silico docking and rational design; (iv) repurposing hepatitis C virus inhibitors for DENV. Along the developmental process from hit finding to clinical candidate, many inhibitors did not advance beyond the stage of hit-to-lead optimization, due to their poor selectivity, physiochemical or pharmacokinetic properties. Only a few compounds showed efficacy in the AG129 DENV mouse model. Two nucleoside analogs, NITD-008 and Balapiravir, entered preclinical animal safety study and clinic trial, but both were terminated due to toxicity and lack of potency, respectively. Celgosivir, a host alpha-glucosidase inhibitor, is currently under clinical trial; its clinical efficacy remains to be determined. The knowledge accumulated during the past decade has provided a better rationale for ongoing dengue drug discovery. Though challenging, we are optimistic that this continuous, concerted effort will lead to an effective dengue therapy.
Novartis Institute for Tropical Diseases, 10 Biopolis Road, 05-01 Chromos, Singapore 138670, Singapore.
Siew Pheng
SP
Lim
Qing-Yin
QY
Wang
Christian G
CG
Noble
Yen-Liang
YL
Chen
Hongping
H
Dong
Bin
B
Zou
Fumiaki
F
Yokokawa
Shahul
S
Nilar
Paul
P
Smith
David
D
Beer
Julien
J
Lescar
Pei-Yong
PY
Shi
D000998:Antiviral Agents / Q000302:isolation & purification*; D003715:Dengue / Q000188:drug therapy* / Q000821:virology*; D003716:Dengue Virus / Q000187:drug effects*; D055808:Drug Discovery / Q000266:history* / Q000639:trends*; D049674:History, 21st Century; D006801:Humans; D012846:Singapore
D000998:Antiviral Agents
Antiviral; DAA; DENV; DHF/DSS; Dengue virus; Drug discovery; ER; FP; Flavivirus; HBV; HCV; HIV; HTS; MTase; NI; NNI; PI; PoC; RNA-dependent RNA polymerase; RdRp; SAR; SPA; TBEV; TI; VSV; WEEV; WNV; West Nile virus; Western equine encephalitis virus; YFV; dengue hemorrhagic fever/dengue shock syndrome; dengue virus; direct antiviral agent; endoplasmic reticulum; fluorescence polarization; hepatitis B virus; hepatitis C virus; high-throughput screening; human immunodeficiency virus; methyltransferase; non-nucleoside inhibitor; nucleoside analog inhibitors; proof-of-concept; protease inhibitors; scintillation proximity assay; structure–activity relationship; therapeutic index; tick-borne encephalitis virus; vesicular stomatitis virus; yellow fever virus