BACKGROUND: Dengue fever, dengue haemorrhagic fever, and dengue shock syndrome are caused by infections with any of the four serotypes of the dengue virus (DENV), and are an increasing global health risk. The related West Nile virus (WNV) causes significant morbidity and mortality as well, and continues to be a threat in endemic areas. Currently no FDA-approved vaccines or therapeutics are available to prevent or treat any of these infections. Like the other members of Flaviviridae, DENV and WNV encode a protease (NS3) which is essential for viral replication and therefore is a promising target for developing therapies to treat dengue and West Nile infections. METHODS: Flaviviral protease inhibitors were identified and biologically characterized for mechanism of inhibition and DENV antiviral activity. RESULTS: A guanidinylated 2,5-dideoxystreptamine class of compounds was identified that competitively inhibited the NS3 protease from DENV(1-4) and WNV with 50% inhibitory concentration values in the 1-70 μM range. Cytotoxicity was low; however, antiviral activity versus DENV-2 on VERO cells was not detectable. CONCLUSIONS: This class of compounds is the first to demonstrate competitive pan-dengue and WNV NS3 protease inhibition and, given the sequence conservation among flavivirus NS3 proteins, suggests that developing a pan-dengue or possibly pan-flavivirus therapeutic is feasible.
BACKGROUND:Dengue fever, dengue haemorrhagic fever, and dengue shock syndrome are caused by infections with any of the four serotypes of the dengue virus (DENV), and are an increasing global health risk. The related West Nile virus (WNV) causes significant morbidity and mortality as well, and continues to be a threat in endemic areas. Currently no FDA-approved vaccines or therapeutics are available to prevent or treat any of these infections. Like the other members of Flaviviridae, DENV and WNV encode a protease (NS3) which is essential for viral replication and therefore is a promising target for developing therapies to treat dengue and West Nile infections. METHODS: Flaviviral protease inhibitors were identified and biologically characterized for mechanism of inhibition and DENV antiviral activity. RESULTS: A guanidinylated 2,5-dideoxystreptamine class of compounds was identified that competitively inhibited the NS3 protease from DENV(1-4) and WNV with 50% inhibitory concentration values in the 1-70 μM range. Cytotoxicity was low; however, antiviral activity versus DENV-2 on VERO cells was not detectable. CONCLUSIONS: This class of compounds is the first to demonstrate competitive pan-dengue and WNVNS3 protease inhibition and, given the sequence conservation among flavivirus NS3 proteins, suggests that developing a pan-dengue or possibly pan-flavivirus therapeutic is feasible.
Authors: Youla S Tsantrizos; Gordon Bolger; Pierre Bonneau; Dale R Cameron; Nathalie Goudreau; George Kukolj; Steven R LaPlante; Montse Llinàs-Brunet; Herbert Nar; Daniel Lamarre Journal: Angew Chem Int Ed Engl Date: 2003-03-28 Impact factor: 15.336
Authors: Jun Li; Siew Pheng Lim; David Beer; Viral Patel; Daying Wen; Christine Tumanut; David C Tully; Jennifer A Williams; Jan Jiricek; John P Priestle; Jennifer L Harris; Subhash G Vasudevan Journal: J Biol Chem Date: 2005-06-01 Impact factor: 5.157
Authors: Ashok Arasappan; Frank Bennett; Stephane L Bogen; Srikanth Venkatraman; Melissa Blackman; Kevin X Chen; Siska Hendrata; Yuhua Huang; Regina M Huelgas; Latha Nair; Angela I Padilla; Weidong Pan; Russell Pike; Patrick Pinto; Sumei Ruan; Mousumi Sannigrahi; Francisco Velazquez; Bancha Vibulbhan; Wanli Wu; Weiying Yang; Anil K Saksena; Viyyoor Girijavallabhan; Neng-Yang Shih; Jianshe Kong; Tao Meng; Yan Jin; Jesse Wong; Paul McNamara; Andrew Prongay; Vincent Madison; John J Piwinski; Kuo-Chi Cheng; Richard Morrison; Bruce Malcolm; Xiao Tong; Robert Ralston; F George Njoroge Journal: ACS Med Chem Lett Date: 2010-02-15 Impact factor: 4.345
Authors: P Ingallinella; S Altamura; E Bianchi; M Taliani; R Ingenito; R Cortese; R De Francesco; C Steinkühler; A Pessi Journal: Biochemistry Date: 1998-06-23 Impact factor: 3.162
Authors: Erika Piccirillo; Benjamin Merget; Christoph A Sotriffer; Antonia T do Amaral Journal: J Comput Aided Mol Des Date: 2016-02-29 Impact factor: 3.686
Authors: Kok-Chuan Tiew; Dengfeng Dou; Tadahisa Teramoto; Huiguo Lai; Kevin R Alliston; Gerald H Lushington; R Padmanabhan; William C Groutas Journal: Bioorg Med Chem Date: 2011-12-30 Impact factor: 3.641
Authors: Sridhar Aravapalli; Huiguo Lai; Tadahisa Teramoto; Kevin R Alliston; Gerald H Lushington; Eron L Ferguson; R Padmanabhan; William C Groutas Journal: Bioorg Med Chem Date: 2012-05-10 Impact factor: 3.641
Authors: Szymon Pach; Tim M Sarter; Rafe Yousef; David Schaller; Silke Bergemann; Christoph Arkona; Jörg Rademann; Christoph Nitsche; Gerhard Wolber Journal: ACS Med Chem Lett Date: 2020-03-03 Impact factor: 4.345
Authors: Hugo de Almeida; Izabela M D Bastos; Bergmann M Ribeiro; Bernard Maigret; Jaime M Santana Journal: PLoS One Date: 2013-08-21 Impact factor: 3.240