Sivakoteswara Rao Mandadapu
Wichita State University
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Publication
Featured researches published by Sivakoteswara Rao Mandadapu.
Journal of Virology | 2012
Yunjeong Kim; Scott Lovell; Kok-Chuan Tiew; Sivakoteswara Rao Mandadapu; Kevin R. Alliston; Kevin P. Battaile; William C. Groutas; Kyeong-Ok Chang
ABSTRACT Phylogenetic analysis has demonstrated that some positive-sense RNA viruses can be classified into the picornavirus-like supercluster, which includes picornaviruses, caliciviruses, and coronaviruses. These viruses possess 3C or 3C-like proteases (3Cpro or 3CLpro, respectively), which contain a typical chymotrypsin-like fold and a catalytic triad (or dyad) with a Cys residue as a nucleophile. The conserved key sites of 3Cpro or 3CLpro may serve as attractive targets for the design of broad-spectrum antivirals for multiple viruses in the supercluster. We previously reported the structure-based design and synthesis of potent protease inhibitors of Norwalk virus (NV), a member of the Caliciviridae family. We report herein the broad-spectrum antiviral activities of three compounds possessing a common dipeptidyl residue with different warheads, i.e., an aldehyde (GC373), a bisulfite adduct (GC376), and an α-ketoamide (GC375), against viruses that belong to the supercluster. All compounds were highly effective against the majority of tested viruses, with half-maximal inhibitory concentrations in the high nanomolar or low micromolar range in enzyme- and/or cell-based assays and with high therapeutic indices. We also report the high-resolution X-ray cocrystal structures of NV 3CLpro-, poliovirus 3Cpro-, and transmissible gastroenteritis virus 3CLpro- GC376 inhibitor complexes, which show the compound covalently bound to a nucleophilic Cys residue in the catalytic site of the corresponding protease. We conclude that these compounds have the potential to be developed as antiviral therapeutics aimed at a single virus or multiple viruses in the picornavirus-like supercluster by targeting 3Cpro or 3CLpro.
Bioorganic & Medicinal Chemistry Letters | 2011
Kok-Chuan Tiew; Guijia He; Sridhar Aravapalli; Sivakoteswara Rao Mandadapu; Mallikarjuna Reddy Gunnam; Kevin R. Alliston; Gerald H. Lushington; Yunjeong Kim; Kyeong-Ok Chang; William C. Groutas
The first series of peptidyl aldehyde inhibitors that incorporate in their structure a glutamine surrogate has been designed and synthesized based on the known substrate specificity of Norwalk virus 3C protease. The inhibitory activity of the compounds with the protease and with a norovirus cell-based replicon system was investigated. Members of this class of compounds exhibited noteworthy activity both in vitro and in a cell-based replicon system.
Bioorganic & Medicinal Chemistry Letters | 2013
Sivakoteswara Rao Mandadapu; Mallikarjuna Reddy Gunnam; Kok-Chuan Tiew; Roxanne Adeline Z. Uy; Allan M. Prior; Kevin R. Alliston; Duy H. Hua; Yunjeong Kim; Kyeong-Ok Chang; William C. Groutas
Noroviruses are the most common cause of acute viral gastroenteritis, accounting for >21 million cases annually in the US alone. Norovirus infections constitute an important health problem for which there are no specific antiviral therapeutics or vaccines. In this study, a series of bisulfite adducts derived from representative transition state inhibitors (dipeptidyl aldehydes and α-ketoamides) was synthesized and shown to exhibit anti-norovirus activity in a cell-based replicon system. The ED(50) of the most effective inhibitor was 60 nM. This study demonstrates for the first time the utilization of bisulfite adducts of transition state inhibitors in the inhibition of norovirus 3C-like protease in vitro and in a cell-based replicon system. The approach described herein can be extended to the synthesis of the bisulfite adducts of other classes of transition state inhibitors of serine and cysteine proteases, such as α-ketoheterocycles and α-ketoesters.
Bioorganic & Medicinal Chemistry Letters | 2012
Sivakoteswara Rao Mandadapu; Pathum M. Weerawarna; Mallikarjuna Reddy Gunnam; Kevin R. Alliston; Gerald H. Lushington; Yunjeong Kim; Kyeong-Ok Chang; William C. Groutas
A series of structurally-diverse α-ketoamides and α-ketoheterocycles was synthesized and subsequently investigated for inhibitory activity against norovirus 3CL protease in vitro, as well as anti-norovirus activity in a cell-based replicon system. The synthesized compounds were found to inhibit norovirus 3CL protease in vitro and to also exhibit potent anti-norovirus activity in a cell-based replicon system.
Bioorganic & Medicinal Chemistry | 2011
Dengfeng Dou; Sivakoteswara Rao Mandadapu; Kevin R. Alliston; Yunjeong Kim; Kyeong-Ok Chang; William C. Groutas
A scaffold hopping strategy was employed to identify new chemotypes that inhibit noroviruses. The replacement of the cyclosulfamide scaffold by an array of heterocyclic scaffolds lead to the identification of additional series of compounds that possessed anti-norovirus activity in a cell-based replicon system.
Journal of Medicinal Chemistry | 2015
Anushka C. Galasiti Kankanamalage; Yunjeong Kim; Pathum M. Weerawarna; Roxanne Adeline Z. Uy; Vishnu C. Damalanka; Sivakoteswara Rao Mandadapu; Kevin R. Alliston; Nurjahan Mehzabeen; Kevin P. Battaile; Scott Lovell; Kyeong-Ok Chang; William C. Groutas
Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of antinorovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection.
Bioorganic & Medicinal Chemistry Letters | 2012
Dengfeng Dou; Guijia He; Sivakoteswara Rao Mandadapu; Sridhar Aravapalli; Yunjeong Kim; Kyeong-Ok Chang; William C. Groutas
There is currently an unmet need for the development of small-molecule therapeutics for norovirus infection. The piperazine scaffold, a privileged structure embodied in many pharmacological agents, was used to synthesize an array of structurally-diverse derivatives which were screened for anti-norovius activity in a cell-based replicon system. The studies described herein demonstrate for the first time that functionalized piperazine derivatives possess anti-norovirus activity. Furthermore, these studies have led to the identification of two promising compounds (6a and 9l) that can be used as a launching pad for the optimization of potency, cytotoxicity, and drug-like characteristics.
Bioorganic & Medicinal Chemistry | 2011
Dengfeng Dou; Kok-Chuan Tiew; Guijia He; Sivakoteswara Rao Mandadapu; Sridhar Aravapalli; Kevin R. Alliston; Yunjeong Kim; Kyeong-Ok Chang; William C. Groutas
A new class of compounds that exhibit anti-norovirus activity in a cell-based system and embody in their structure a cyclosulfamide scaffold has been identified. The structure of the initial hit (compound 2a, ED(50) 4 μM, TD(50) 50 μM) has been prospected by exploiting multiple points of diversity and generating appropriate structure-activity relationships.
Bioorganic & Medicinal Chemistry Letters | 2013
Sivakoteswara Rao Mandadapu; Pathum M. Weerawarna; Allan M. Prior; Roxanne Adeline Z. Uy; Sridhar Aravapalli; Kevin R. Alliston; Gerald H. Lushington; Yunjeong Kim; Duy H. Hua; Kyeong-Ok Chang; William C. Groutas
Abstract The design, synthesis, and in vitro evaluation of the first macrocyclic inhibitor of 3C and 3C-like proteases of picornavirus, norovirus, and coronavirus are reported. The in vitro inhibitory activity (50% effective concentration) of the macrocyclic inhibitor toward enterovirus 3C protease (CVB3 Nancy strain), and coronavirus (SARS-CoV) and norovirus 3C-like proteases, was determined to be 1.8, 15.5 and 5.1μM, respectively.
Bioorganic & Medicinal Chemistry | 2011
Dengfeng Dou; Deepu Alex; Bingfan Du; Kok-Chuan Tiew; Sridhar Aravapalli; Sivakoteswara Rao Mandadapu; Richard Calderone; William C. Groutas
A series of broad-spectrum antifungal agents based on the 1,2-benzisothiazol-3(2H)-one scaffold is reported. Preliminary structure-activity relationship studies have established the importance of the presence of the heterocyclic ring, a methyl group, and a phenyl ring for optimal manifestation of antifungal activity.