Mallikarjuna Putta - Academia.edu (original) (raw)
Uploads
Papers by Mallikarjuna Putta
L'invention concerne l'utilisation therapeutique d'oligoribonucleotides stabilises co... more L'invention concerne l'utilisation therapeutique d'oligoribonucleotides stabilises comme agents immunomodulateurs pour applications immunotherapeutiques. Plus particulierement, l'invention concerne des oligoribonucleotides a base d'ARN presentant une stabilite nucleasique et RNasique accrue et une activite immunomodulatrice a travers TLR7 et/ou TLR8.
L’invention concerne des composes oligonucleotides antisens, des compositions et des procedes per... more L’invention concerne des composes oligonucleotides antisens, des compositions et des procedes permettant la regulation negative de l’expression de TLR9. Les compositions comprennent des oligonucleotides antisens diriges contre les acides nucleiques codant TLR9. Les compositions peuvent egalement comprendre des oligonucleotides antisens diriges contre les acides nucleiques codant TLR9 en combinaison avec d’autres composes et/ou compositions therapeutiques et/ou prophylactiques. L’invention porte sur des procedes d’utilisation desdits composes et compositions permettant la regulation negative de l’expression de TLR9 et permettant le traitement ou la prevention de maladies pour lesquelles la modulation de l’expression de TLR9 s’avere benefique.
Proceedings of the National Academy of Sciences, 2007
Viral and synthetic single-stranded RNAs are the ligands for Toll-like receptor (TLR)7 and TLR8. ... more Viral and synthetic single-stranded RNAs are the ligands for Toll-like receptor (TLR)7 and TLR8. However, single-stranded RNA is rapidly degraded by ubiquitous RNases, and the studies reported to date have used RNA with lipid carriers. To overcome nuclease susceptibility of RNA, we have synthesized several RNAs incorporating a range of chemical modifications. The present study describes one pool of RNA compounds, referred to as stabilized immune modulatory RNA (SIMRA) compounds, in which two RNA segments are attached through their 3′ ends. SIMRA compounds showed greater stability in human serum compared with linear RNA and activated human TLR8, but not TLR7, in HEK293 cells without using lipid carriers. Interestingly, another set of SIMRA compounds containing 7-deazaguanosine substituted for natural guanosine activated human TLR7 and TLR8. Additionally, TLR7- and TLR8-activating compounds, but not the compounds that activated only TLR8, stimulated mouse immune cells in vitro and in ...
L'invention concerne l'utilisation therapeutique d'oligoribonucleotides stabilises co... more L'invention concerne l'utilisation therapeutique d'oligoribonucleotides stabilises comme agents immunomodulateurs pour applications immunotherapeutiques. Plus particulierement, l'invention concerne des oligoribonucleotides a base d'ARN presentant une stabilite nucleasique et RNasique accrue et une activite immunomodulatrice a travers TLR7 et/ou TLR8.
L’invention concerne des composes oligonucleotides antisens, des compositions et des procedes per... more L’invention concerne des composes oligonucleotides antisens, des compositions et des procedes permettant la regulation negative de l’expression de TLR9. Les compositions comprennent des oligonucleotides antisens diriges contre les acides nucleiques codant TLR9. Les compositions peuvent egalement comprendre des oligonucleotides antisens diriges contre les acides nucleiques codant TLR9 en combinaison avec d’autres composes et/ou compositions therapeutiques et/ou prophylactiques. L’invention porte sur des procedes d’utilisation desdits composes et compositions permettant la regulation negative de l’expression de TLR9 et permettant le traitement ou la prevention de maladies pour lesquelles la modulation de l’expression de TLR9 s’avere benefique.
Proceedings of the National Academy of Sciences, 2007
Viral and synthetic single-stranded RNAs are the ligands for Toll-like receptor (TLR)7 and TLR8. ... more Viral and synthetic single-stranded RNAs are the ligands for Toll-like receptor (TLR)7 and TLR8. However, single-stranded RNA is rapidly degraded by ubiquitous RNases, and the studies reported to date have used RNA with lipid carriers. To overcome nuclease susceptibility of RNA, we have synthesized several RNAs incorporating a range of chemical modifications. The present study describes one pool of RNA compounds, referred to as stabilized immune modulatory RNA (SIMRA) compounds, in which two RNA segments are attached through their 3′ ends. SIMRA compounds showed greater stability in human serum compared with linear RNA and activated human TLR8, but not TLR7, in HEK293 cells without using lipid carriers. Interestingly, another set of SIMRA compounds containing 7-deazaguanosine substituted for natural guanosine activated human TLR7 and TLR8. Additionally, TLR7- and TLR8-activating compounds, but not the compounds that activated only TLR8, stimulated mouse immune cells in vitro and in ...
Journal of Medicinal Chemistry, 2007
Journal of Medicinal Chemistry, 2007
Cellular Immunology, 2010
Novel agonists of TLR9 with two 5&amp... more Novel agonists of TLR9 with two 5'-ends and synthetic immune stimulatory motifs, referred to as immune modulatory oligonucleotides (IMOs) are potent agonists of TLR9. In the present study, we have designed and synthesized 15 novel IMOs by incorporating specific chemical modifications and studied their immune response profiles both in vitro and in vivo. Analysis of the immunostimulatory profiles of these IMOs in human and NHP cell-based assays suggest that changes in the number of synthetic immunostimulatory motifs gave only a subtle change in immune stimulation of pDCs as indicated by IFN-alpha production and pDC maturation while the addition of self-complementary sequences produced more dramatic changes in both pDC and B cell stimulation. All IMOs induced cytokine production in vivo immediately after administration in mice. Representative compounds were also compared for the ability to stimulate cytokine production in vivo (IFN-alpha and IP-10) in rhesus macaques after intra-muscular administration.
Biochemical and Biophysical Research Communications, 2009
Single-stranded RNAs act as ligands of Toll-like receptors (TLRs) 7 and 8 and induce immune respo... more Single-stranded RNAs act as ligands of Toll-like receptors (TLRs) 7 and 8 and induce immune responses. In the present study, we have designed and synthesized phosphorothioate oligoribonucleotides (ORNs) with self-complementary sequences that form duplex structures with either 3'- or 5'-overhanging sequences. We studied the new ORNs for their duplex formation, nuclease stability, and ability to induce immune-stimulatory activate through TLR7 and TLR8 in TLR-transfected cell lines, human PBMCs, human pDCs, and in vivo in mice. Thermal melting and gel electrophoresis studies showed that all ORNs formed secondary structures and that the thermal stability of the duplex is depended on the length and GC composition of the duplex. Nuclease stability of ORNs increased with increasing thermal stability of the duplex formed. All ORN showed TLR8 activity in HEK293 cells, and induced cytokine and chemokine production in human PBMC cultures. In addition to TLR8 activity, two ORNs containing a 'CUGAAUU' motif in the duplex-forming region induced immune stimulation through TLR7 in HEK293 cells, human PBMC and pDC cultures, and in vivo in mice. These results suggest that secondary structures in ORN provide nuclease stability and lead to stimulation of immune responses through TLR8 as well as TLR7 depending on the presence of specific nucleotide motifs.
Antimicrobial Agents and Chemotherapy, 2008
Oligodeoxynucleotides containing a CpG motif and double- or multistranded structure-forming seque... more Oligodeoxynucleotides containing a CpG motif and double- or multistranded structure-forming sequences act as agonists of Toll-like receptor 9 (TLR9) and induce high levels of interferon alpha (IFN-α) in addition to other Th1-type cytokines. In the present study, we evaluated three highly effective IFN-α-inducing agonists of TLR9 to determine the type of duplex structures formed and the agonist's ability to induce immune responses, including IFN-α induction, in human cell-based assays and in vivo in mice and nonhuman primates. Thermal melting studies showed that two of the agonists evaluated had a single melting transition with similar hyperchromicity in both heating and cooling cycles, suggesting the formation of intermolecular duplexes. A third agonist showed a biphasic melting transition in the heating cycle and a monophasic melting transition with lower hyperchromicity during the cooling cycle, suggesting the formation of both intra- and intermolecular duplexes. All three ago...
ACS Medicinal Chemistry Letters, 2013
Oligodeoxynucleotides (ODNs) containing a CpG or certain synthetic dinucleotides, referred to as ... more Oligodeoxynucleotides (ODNs) containing a CpG or certain synthetic dinucleotides, referred to as immunestimulatory dinucleotides, induce Toll-like receptor 9 (TLR9)mediated immune responses. Chemical modifications such as 2′-O-methylribonucleotides incorporated adjacent to the immune-stimulatory dinucleotide on the 5′-side abrogate TLR9mediated immune responses. In this study, we evaluated the effect of the location of immune-stimulatory dinucleotides in ODNs on TLR9-mediated immune responses. We designed and synthesized ODNs with two immune-stimulatory dinucleotides, one placed toward the 5′-end region and the other toward the 3′-end region, incorporated 2′-O-methylribonucleotides selectively preceding the 5′-or 3′-immune-stimulatory dinucleotide or both, and studied TLR9-mediated immune responses of these compounds in cell-based assays and in vivo in mice. These studies showed that an immune-stimulatory dinucleotide located closer to the 5′-end is critical for and dictates TLR9-mediated immune responses. These studies provide insights for the use of ODNs when employed as TLR9 agonists and antagonists or antisense agents.
Journal of Medicinal Chemistry, 2011
L'invention concerne l'utilisation therapeutique d'oligoribonucleotides stabilises co... more L'invention concerne l'utilisation therapeutique d'oligoribonucleotides stabilises comme agents immunomodulateurs pour applications immunotherapeutiques. Plus particulierement, l'invention concerne des oligoribonucleotides a base d'ARN presentant une stabilite nucleasique et RNasique accrue et une activite immunomodulatrice a travers TLR7 et/ou TLR8.
L’invention concerne des composes oligonucleotides antisens, des compositions et des procedes per... more L’invention concerne des composes oligonucleotides antisens, des compositions et des procedes permettant la regulation negative de l’expression de TLR9. Les compositions comprennent des oligonucleotides antisens diriges contre les acides nucleiques codant TLR9. Les compositions peuvent egalement comprendre des oligonucleotides antisens diriges contre les acides nucleiques codant TLR9 en combinaison avec d’autres composes et/ou compositions therapeutiques et/ou prophylactiques. L’invention porte sur des procedes d’utilisation desdits composes et compositions permettant la regulation negative de l’expression de TLR9 et permettant le traitement ou la prevention de maladies pour lesquelles la modulation de l’expression de TLR9 s’avere benefique.
Proceedings of the National Academy of Sciences, 2007
Viral and synthetic single-stranded RNAs are the ligands for Toll-like receptor (TLR)7 and TLR8. ... more Viral and synthetic single-stranded RNAs are the ligands for Toll-like receptor (TLR)7 and TLR8. However, single-stranded RNA is rapidly degraded by ubiquitous RNases, and the studies reported to date have used RNA with lipid carriers. To overcome nuclease susceptibility of RNA, we have synthesized several RNAs incorporating a range of chemical modifications. The present study describes one pool of RNA compounds, referred to as stabilized immune modulatory RNA (SIMRA) compounds, in which two RNA segments are attached through their 3′ ends. SIMRA compounds showed greater stability in human serum compared with linear RNA and activated human TLR8, but not TLR7, in HEK293 cells without using lipid carriers. Interestingly, another set of SIMRA compounds containing 7-deazaguanosine substituted for natural guanosine activated human TLR7 and TLR8. Additionally, TLR7- and TLR8-activating compounds, but not the compounds that activated only TLR8, stimulated mouse immune cells in vitro and in ...
L'invention concerne l'utilisation therapeutique d'oligoribonucleotides stabilises co... more L'invention concerne l'utilisation therapeutique d'oligoribonucleotides stabilises comme agents immunomodulateurs pour applications immunotherapeutiques. Plus particulierement, l'invention concerne des oligoribonucleotides a base d'ARN presentant une stabilite nucleasique et RNasique accrue et une activite immunomodulatrice a travers TLR7 et/ou TLR8.
L’invention concerne des composes oligonucleotides antisens, des compositions et des procedes per... more L’invention concerne des composes oligonucleotides antisens, des compositions et des procedes permettant la regulation negative de l’expression de TLR9. Les compositions comprennent des oligonucleotides antisens diriges contre les acides nucleiques codant TLR9. Les compositions peuvent egalement comprendre des oligonucleotides antisens diriges contre les acides nucleiques codant TLR9 en combinaison avec d’autres composes et/ou compositions therapeutiques et/ou prophylactiques. L’invention porte sur des procedes d’utilisation desdits composes et compositions permettant la regulation negative de l’expression de TLR9 et permettant le traitement ou la prevention de maladies pour lesquelles la modulation de l’expression de TLR9 s’avere benefique.
Proceedings of the National Academy of Sciences, 2007
Viral and synthetic single-stranded RNAs are the ligands for Toll-like receptor (TLR)7 and TLR8. ... more Viral and synthetic single-stranded RNAs are the ligands for Toll-like receptor (TLR)7 and TLR8. However, single-stranded RNA is rapidly degraded by ubiquitous RNases, and the studies reported to date have used RNA with lipid carriers. To overcome nuclease susceptibility of RNA, we have synthesized several RNAs incorporating a range of chemical modifications. The present study describes one pool of RNA compounds, referred to as stabilized immune modulatory RNA (SIMRA) compounds, in which two RNA segments are attached through their 3′ ends. SIMRA compounds showed greater stability in human serum compared with linear RNA and activated human TLR8, but not TLR7, in HEK293 cells without using lipid carriers. Interestingly, another set of SIMRA compounds containing 7-deazaguanosine substituted for natural guanosine activated human TLR7 and TLR8. Additionally, TLR7- and TLR8-activating compounds, but not the compounds that activated only TLR8, stimulated mouse immune cells in vitro and in ...
Journal of Medicinal Chemistry, 2007
Journal of Medicinal Chemistry, 2007
Cellular Immunology, 2010
Novel agonists of TLR9 with two 5&amp... more Novel agonists of TLR9 with two 5'-ends and synthetic immune stimulatory motifs, referred to as immune modulatory oligonucleotides (IMOs) are potent agonists of TLR9. In the present study, we have designed and synthesized 15 novel IMOs by incorporating specific chemical modifications and studied their immune response profiles both in vitro and in vivo. Analysis of the immunostimulatory profiles of these IMOs in human and NHP cell-based assays suggest that changes in the number of synthetic immunostimulatory motifs gave only a subtle change in immune stimulation of pDCs as indicated by IFN-alpha production and pDC maturation while the addition of self-complementary sequences produced more dramatic changes in both pDC and B cell stimulation. All IMOs induced cytokine production in vivo immediately after administration in mice. Representative compounds were also compared for the ability to stimulate cytokine production in vivo (IFN-alpha and IP-10) in rhesus macaques after intra-muscular administration.
Biochemical and Biophysical Research Communications, 2009
Single-stranded RNAs act as ligands of Toll-like receptors (TLRs) 7 and 8 and induce immune respo... more Single-stranded RNAs act as ligands of Toll-like receptors (TLRs) 7 and 8 and induce immune responses. In the present study, we have designed and synthesized phosphorothioate oligoribonucleotides (ORNs) with self-complementary sequences that form duplex structures with either 3'- or 5'-overhanging sequences. We studied the new ORNs for their duplex formation, nuclease stability, and ability to induce immune-stimulatory activate through TLR7 and TLR8 in TLR-transfected cell lines, human PBMCs, human pDCs, and in vivo in mice. Thermal melting and gel electrophoresis studies showed that all ORNs formed secondary structures and that the thermal stability of the duplex is depended on the length and GC composition of the duplex. Nuclease stability of ORNs increased with increasing thermal stability of the duplex formed. All ORN showed TLR8 activity in HEK293 cells, and induced cytokine and chemokine production in human PBMC cultures. In addition to TLR8 activity, two ORNs containing a 'CUGAAUU' motif in the duplex-forming region induced immune stimulation through TLR7 in HEK293 cells, human PBMC and pDC cultures, and in vivo in mice. These results suggest that secondary structures in ORN provide nuclease stability and lead to stimulation of immune responses through TLR8 as well as TLR7 depending on the presence of specific nucleotide motifs.
Antimicrobial Agents and Chemotherapy, 2008
Oligodeoxynucleotides containing a CpG motif and double- or multistranded structure-forming seque... more Oligodeoxynucleotides containing a CpG motif and double- or multistranded structure-forming sequences act as agonists of Toll-like receptor 9 (TLR9) and induce high levels of interferon alpha (IFN-α) in addition to other Th1-type cytokines. In the present study, we evaluated three highly effective IFN-α-inducing agonists of TLR9 to determine the type of duplex structures formed and the agonist's ability to induce immune responses, including IFN-α induction, in human cell-based assays and in vivo in mice and nonhuman primates. Thermal melting studies showed that two of the agonists evaluated had a single melting transition with similar hyperchromicity in both heating and cooling cycles, suggesting the formation of intermolecular duplexes. A third agonist showed a biphasic melting transition in the heating cycle and a monophasic melting transition with lower hyperchromicity during the cooling cycle, suggesting the formation of both intra- and intermolecular duplexes. All three ago...
ACS Medicinal Chemistry Letters, 2013
Oligodeoxynucleotides (ODNs) containing a CpG or certain synthetic dinucleotides, referred to as ... more Oligodeoxynucleotides (ODNs) containing a CpG or certain synthetic dinucleotides, referred to as immunestimulatory dinucleotides, induce Toll-like receptor 9 (TLR9)mediated immune responses. Chemical modifications such as 2′-O-methylribonucleotides incorporated adjacent to the immune-stimulatory dinucleotide on the 5′-side abrogate TLR9mediated immune responses. In this study, we evaluated the effect of the location of immune-stimulatory dinucleotides in ODNs on TLR9-mediated immune responses. We designed and synthesized ODNs with two immune-stimulatory dinucleotides, one placed toward the 5′-end region and the other toward the 3′-end region, incorporated 2′-O-methylribonucleotides selectively preceding the 5′-or 3′-immune-stimulatory dinucleotide or both, and studied TLR9-mediated immune responses of these compounds in cell-based assays and in vivo in mice. These studies showed that an immune-stimulatory dinucleotide located closer to the 5′-end is critical for and dictates TLR9-mediated immune responses. These studies provide insights for the use of ODNs when employed as TLR9 agonists and antagonists or antisense agents.
Journal of Medicinal Chemistry, 2011