A synthesis of the first-in-class pan-serotype dengue virus inhibitor NITD-688 is presented. The Gewald reaction of N-(tert-butoxycarbonyl)-6,6-dimethylpiperidin-3-one with malononitrile and sulfur in the presence of l-proline as a catalyst gave tert-butyl 2-amino-3-cyano-6,6-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate. This was coupled with [4-(aminosulfonyl)phenyl]acetic acid by using propanephosphonic acid anhydride. A subsequent reductive alkylation with cyclohexanecarboxaldehyde gave NITD-688. Preliminary results of our attempts to control the regioselectivity of the Gewald synthesis of the 2-amino-3-cyanothiophene core are also presented.

03 Feb 2021·Science Translational MedicineQ1 · MEDICINE

NITD-688, a pan-serotype inhibitor of the dengue virus NS4B protein, shows favorable pharmacokinetics and efficacy in preclinical animal models

Q1 · MEDICINE

Article

Author: Sasseville, Vito G. ; Wan, Kah Fei ; Song, Jae-Geun ; Lakshminarayana, Suresh B. ; Wang, Feng ; Gu, Feng ; Liu, Wei ; Barkan, David T. ; Chan, Wai Ling ; Seh, Cheah Chen ; Sim, Wei Lin Sandra ; Wang, Qing-Yin ; Zou, Bin ; Li, Min ; Lu, Siyan ; Sarko, Christopher ; Bonamy, Ghislain M. C. ; Karuna, Ratna ; Lim, Siew Pheng ; Kounde, Cyrille S. ; Wang, Gang ; Day, Craig W. ; Chen, Yen-Liang ; Saravanan, Chandra ; Diagana, Thierry T. ; Yokokawa, Fumiaki ; Moquin, Stephanie A. ; Chan, Katherine ; Yeo, Hui-Quan ; Beer, David ; Yeung, Bryan K. S. ; Blasco, Francesca ; Simon, Oliver ; Dong, Hongping ; Osborne, Colin ; Zhang, Jin ; Ding, Mei ; Xu, Haoying ; Shi, Pei-Yong

NITD-688, a pan-serotype dengue virus inhibitor, is effective in mice and is well tolerated with favorable pharmacokinetics in animal models.

Nature Communications

Pan-serotype dengue virus inhibitor JNJ-A07 targets NS4A-2K-NS4B interaction with NS2B/NS3 and blocks replication organelle formation

Article

Author: Geluykens, Peggy ; Kiemel, Dominik ; Ghosh, Brahma ; Denolly, Solène ; Kaptein, Suzanne J F ; Haselmann, Uta ; Andres, Jose Ignacio ; Kroell, Ann-Sophie Helene ; Bonfanti, Jean-François ; Bartenschlager, Ralf ; Van Loock, Marnix ; Wilken, Lucas ; Scaturro, Pietro ; Neyts, Johan ; Goethals, Olivia

AbstractDengue fever represents a significant medical and socio-economic burden in (sub)tropical regions, yet antivirals for treatment or prophylaxis are lacking. JNJ-A07 was described as highly active against the different genotypes within each serotype of the disease-causing dengue virus (DENV). Based on clustering of resistance mutations it has been assumed to target DENV non-structural protein 4B (NS4B). Using a photoaffinity labeling compound with high structural similarity to JNJ-A07, here we demonstrate binding to NS4B and its precursor NS4A-2K-NS4B. Consistently, we report recruitment of the compound to intracellular sites enriched for these proteins. We further specify the mechanism-of-action of JNJ-A07, which has virtually no effect on viral polyprotein cleavage, but targets the interaction between the NS2B/NS3 protease/helicase complex and the NS4A-2K-NS4B cleavage intermediate. This interaction is functionally linked to de novo formation of vesicle packets (VPs), the sites of DENV RNA replication. JNJ-A07 blocks VPs biogenesis with little effect on established ones. A similar mechanism-of-action was found for another NS4B inhibitor, NITD-688. In summary, we unravel the antiviral mechanism of these NS4B-targeting molecules and show how DENV employs a short-lived cleavage intermediate to carry out an early step of the viral life cycle.

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Hepatitis C	Preclinical	Switzerland	Novartis AG	03 Nov 2021

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