Ravikumar Jimmidi | Baylor College of Medicine (original) (raw)
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Papers by Ravikumar Jimmidi
Nanoscale
Glycofullerenes can be grafted at the surface of gold nanoparticles of various sizes. The resulti... more Glycofullerenes can be grafted at the surface of gold nanoparticles of various sizes. The resulting glycoC60-AuNPs can tightly bind key receptors of viral and bacterial infections in a size-dependent manner.
European Journal of Organic Chemistry
European Journal of Organic Chemistry, 2014
Mitochondria produce the majority of cellular energy through the process of oxidative phosphoryla... more Mitochondria produce the majority of cellular energy through the process of oxidative phosphorylation and play a central role in regulating the functionality and survival of eukaryotic cells. Under physiological stress, mitochondrial membrane permeabilization results in the release of apoptogenic material such as cytochrome c in the cytoplasm, which thereby initiates caspase activation and the consequent cell death. In our present study, we screened a series of compounds for their ability to inhibit mitochondrial membrane permeabilization and to prevent cytochrome c release during the endoplasmic reticulum stress in cultured pancre-[a] Dr.
Chemical Reviews, 2014
ABSTRACT Some case studies for small molecule modulators of protein-protein interactions (PPI) ar... more ABSTRACT Some case studies for small molecule modulators of protein-protein interactions (PPI) are reviewed. It has been shown that in general natural products are proven to be highly effective in modulating PPI, and in many cases, this is achieved through the interactions utilizing the allosteric sites. As shown through some specific case studies, the structural information about the PP interface has also been highly useful in designing synthetic compounds. There is a growth in activity in building chemical toolboxes having compounds that are closer to bioactive natural products. This would also challenge the synthetic community to develop new approaches to access a wide variety of natural product-like or natural product inspired scaffolds. One such area that is gaining momentum is to establish methods that allows building the macrocyclic-based chemical toolboxes. Discovery of functional small molecule modulators of PPI demands a close interaction of the synthesis community working closely with other skill sets that are specialized in various aspects of studying these interactions.
Communications Chemistry
The development of SARS-CoV-2 main protease (Mpro) inhibitors for the treatment of COVID-19 has m... more The development of SARS-CoV-2 main protease (Mpro) inhibitors for the treatment of COVID-19 has mostly benefitted from X-ray structures and preexisting knowledge of inhibitors; however, an efficient method to generate Mpro inhibitors, which circumvents such information would be advantageous. As an alternative approach, we show here that DNA-encoded chemistry technology (DEC-Tec) can be used to discover inhibitors of Mpro. An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using Mpro as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of Mpro with low nanomolar Ki values. Furthermore, these compounds demonstrate efficacy against mutant forms of Mpro that have shown resistance to the standard-of-care drug nirmatrelvir. Overall, this work demonstrates that DEC-Tec can efficiently generate novel and potent inhibitors without preliminary chemical or structural information.
Nature Communications
The recent emergence of highly transmissible SARS-CoV-2 variants illustrates the urgent need to b... more The recent emergence of highly transmissible SARS-CoV-2 variants illustrates the urgent need to better understand the molecular details of the virus binding to its host cell and to develop anti-viral strategies. While many studies focused on the role of the angiotensin-converting enzyme 2 receptor in the infection, others suggest the important role of cell attachment factors such as glycans. Here, we use atomic force microscopy to study these early binding events with the focus on the role of sialic acids (SA). We show that SARS-CoV-2 binds specifically to 9-O-acetylated-SA with a moderate affinity, supporting its role as an attachment factor during virus landing to cell host surfaces. For therapeutic purposes and based on this finding, we have designed novel blocking molecules with various topologies and carrying a controlled number of SA residues, enhancing affinity through a multivalent effect. Inhibition assays show that the AcSA-derived glycoclusters are potent inhibitors of ce...
Journal of medicinal chemistry, 2021
Pseudomonas aeruginosa (P.A.) is a human pathogen belonging to the top priorities for the discove... more Pseudomonas aeruginosa (P.A.) is a human pathogen belonging to the top priorities for the discovery of new therapeutic solutions. Its propensity to generate biofilms strongly complicates the treatments required to cure P.A. infections. Herein, we describe the synthesis of a series of novel rotaxanes composed of a central galactosylated pillar[5]arene, a tetrafucosylated dendron, and a tetraguanidinium subunit. Besides the high affinity of the final glycorotaxanes for the two P.A. lectins LecA and LecB, potent inhibition levels of biofilm growth were evidenced, showing that their three subunits work synergistically. An antibiofilm assay using a double ΔlecAΔlecB mutant compared to the wild type demonstrated that the antibiofilm activity of the best glycorotaxane is lectin-mediated. Such antibiofilm potency had rarely been reached in the literature. Importantly, none of the final rotaxanes was bactericidal, showing that their antibiofilm activity does not depend on bacteria killing, w...
Proceedings of the National Academy of Sciences of the United States of America, 2021
Significance SARS-CoV-2 has had a crippling impact on human life globally. Vaccine development ha... more Significance SARS-CoV-2 has had a crippling impact on human life globally. Vaccine development has been used as a first-line strategy for COVID-19 prevention and mitigation; however, small-molecule drugs are still vitally needed to extend treatment options. Traditional screening methods for identifying biologically active small molecules are sluggish and often sample an insufficient number of compounds to identify suitable hits. Here, we applied a screening method known as DNA-encoded chemistry technology (DEC-Tec) to screen billions of compounds against a critical viral protein, Mpro. In rapid fashion, we identified the compound CDD-1713 as a potent and selective Mpro inhibitor. This study illuminates DEC-Tec as a highly expeditious strategy toward generating small molecules against critical targets of infectious agents. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration...
Modulators of microtubule dynamics have received increasing attention because of their potential ... more Modulators of microtubule dynamics have received increasing attention because of their potential to stop cancer growth. Although it belongs to the category of complex protein-protein interactions (PPIs), which are generally considered difficult to modulate through small molecules, the use of microtubule is considered a well-validated target. There are a number of bioactive natural products and related compounds that are currently in use as drugs or in clinical trials as next generation anti-cancer agents. The present review article is focused on two such bioactive natural products, epothilone and halichondrin B, and covers some of the key papers published after 2005 that outline various synthetic approaches to obtain next generation structural analogs as well as the synthesis of hybrid compounds.
European Journal of Organic Chemistry, 2014
Keywords: Natural products / Macrocycles / Mitochondria / Cell death / Diabetes Mitochondria prod... more Keywords: Natural products / Macrocycles / Mitochondria / Cell death / Diabetes Mitochondria produce the majority of cellular energy through the process of oxidative phosphorylation and play a central role in regulating the functionality and survival of eukaryotic cells. Under physiological stress, mitochondrial membrane permeabilization results in the release of apoptogenic material such as cytochrome c in the cytoplasm, which thereby initiates caspase activation and the conse-quent cell death. In our present study, we screened a series of compounds for their ability to inhibit mitochondrial mem-brane permeabilization and to prevent cytochrome c release during the endoplasmic reticulum stress in cultured
Nature Communications
It is assumed that intracellular pathogenic bacteria have to cope with DNA alkylating stress with... more It is assumed that intracellular pathogenic bacteria have to cope with DNA alkylating stress within host cells. Here we use single-cell reporter systems to show that the pathogenBrucella abortusdoes encounter alkylating stress during the first hours of macrophage infection. Genes encoding direct repair and base-excision repair pathways are required byB. abortusto face this stress in vitro and in a mouse infection model. Among these genes,ogtis found to be under the control of the conserved cell-cycle transcription factor GcrA. Our results highlight that the control of DNA repair inB. abortusdisplays distinct features that are not present in model organisms such asEscherichia coli.
Organic Letters
A stereoselective synthesis of a rapamycin fragment is developed and further utilized toward buil... more A stereoselective synthesis of a rapamycin fragment is developed and further utilized toward building a macrocyclic chemical toolbox. The amino alcohol moiety embedded in the 22-membered macrocyclic ring allowed for the addition of a variation in the chiral side chain. The key reactions leading to the synthesis of the rapamycin-derived pyran fragment include the following: (i) Paterson aldol, (ii) stereoselective β-OH carbonyl reduction, and (iii) regio- and stereoselective intramolecular oxy-Michael reaction. The other piece needed for building the macrocyclic diversity was obtained from the coupling of various amino alcohol moieties with S-pipecolic acid.
Introduction 4641 1.1. Going in for Protein−Protein Interactions and Pathways 4641 1.2. Protein−P... more Introduction 4641 1.1. Going in for Protein−Protein Interactions and Pathways 4641 1.2. Protein−Protein Interactions and Small Molecules 4641 2. Case Study 1: Tubulin Polymerization and Natural Product-Derived Small Molecules 4642 3. Case Study 2: p53 and MDM2 Interactions and Small Molecules 4649 3.1. Natural Product Inhibitors of p53−MDM2 Interactions 4650 3.2. β-Hairpin Peptidomimetics 4652 3.3. Terphenyls 4653 3.4. Nutlins 4653 3.5. Benzodiazepines 4654 3.6. Spiro-oxindoles 4656 3.7. Chromenotriazolopyrimidines 4656 3.8. Piperidinones 4657 3.9. Indolo-imidazoles 4658 4. Case Study 3: Modulation of HSP90-Related Protein−Protein Interactions by Natural Products and Related Compounds 4659 4.1. Structure, Conformation, and Functions of HSP 4659 4.2. Hsp90 Inhibitors 4660 5. Case Study 4: Protein−Protein Interactions Centered on the Inhibitors of Apoptosis Proteins (IAPs) and Synthetic Small Molecules 4666 5.1. Overview of Functions of IAPs 4666 5.2. Death Receptor Pathway of Caspase Activation 4667 5.3. Mitochondrial Pathway of Caspase Activation 4667 5.4. Converging Points and Cross-Talk 4667 5.5. Nonpeptidic Small Molecules 4668 5.5.1. TWX Molecules: First Reported Nonpeptide Inhibitor of XIAP (BIR2 domain) 4668 5.
Organic letters, Jan 12, 2015
A practical stereoselective synthesis to obtain the substituted furan ring as the substructure of... more A practical stereoselective synthesis to obtain the substituted furan ring as the substructure of eribulin is developed. An asymmetric syn-aldol and intramolecular oxy-Michael were two key steps in our approach. The functionalized furan derivatives were then utilized further to build the 14- and 12-membered macrocyclic diversity as trans- and cis-fused (C-29 and C-30) compounds. This is the first report of building a chemical toolbox with macrocyclic small molecules having trans- or cis-fused 14- or 12-membered rings containing the substructure of eribulin and its diastereomer.
ABSTRACT Some case studies for small molecule modulators of protein-protein interactions (PPI) ar... more ABSTRACT Some case studies for small molecule modulators of protein-protein interactions (PPI) are reviewed. It has been shown that in general natural products are proven to be highly effective in modulating PPI, and in many cases, this is achieved through the interactions utilizing the allosteric sites. As shown through some specific case studies, the structural information about the PP interface has also been highly useful in designing synthetic compounds. There is a growth in activity in building chemical toolboxes having compounds that are closer to bioactive natural products. This would also challenge the synthetic community to develop new approaches to access a wide variety of natural product-like or natural product inspired scaffolds. One such area that is gaining momentum is to establish methods that allows building the macrocyclic-based chemical toolboxes. Discovery of functional small molecule modulators of PPI demands a close interaction of the synthesis community working closely with other skill sets that are specialized in various aspects of studying these interactions.
Nanoscale
Glycofullerenes can be grafted at the surface of gold nanoparticles of various sizes. The resulti... more Glycofullerenes can be grafted at the surface of gold nanoparticles of various sizes. The resulting glycoC60-AuNPs can tightly bind key receptors of viral and bacterial infections in a size-dependent manner.
European Journal of Organic Chemistry
European Journal of Organic Chemistry, 2014
Mitochondria produce the majority of cellular energy through the process of oxidative phosphoryla... more Mitochondria produce the majority of cellular energy through the process of oxidative phosphorylation and play a central role in regulating the functionality and survival of eukaryotic cells. Under physiological stress, mitochondrial membrane permeabilization results in the release of apoptogenic material such as cytochrome c in the cytoplasm, which thereby initiates caspase activation and the consequent cell death. In our present study, we screened a series of compounds for their ability to inhibit mitochondrial membrane permeabilization and to prevent cytochrome c release during the endoplasmic reticulum stress in cultured pancre-[a] Dr.
Chemical Reviews, 2014
ABSTRACT Some case studies for small molecule modulators of protein-protein interactions (PPI) ar... more ABSTRACT Some case studies for small molecule modulators of protein-protein interactions (PPI) are reviewed. It has been shown that in general natural products are proven to be highly effective in modulating PPI, and in many cases, this is achieved through the interactions utilizing the allosteric sites. As shown through some specific case studies, the structural information about the PP interface has also been highly useful in designing synthetic compounds. There is a growth in activity in building chemical toolboxes having compounds that are closer to bioactive natural products. This would also challenge the synthetic community to develop new approaches to access a wide variety of natural product-like or natural product inspired scaffolds. One such area that is gaining momentum is to establish methods that allows building the macrocyclic-based chemical toolboxes. Discovery of functional small molecule modulators of PPI demands a close interaction of the synthesis community working closely with other skill sets that are specialized in various aspects of studying these interactions.
Communications Chemistry
The development of SARS-CoV-2 main protease (Mpro) inhibitors for the treatment of COVID-19 has m... more The development of SARS-CoV-2 main protease (Mpro) inhibitors for the treatment of COVID-19 has mostly benefitted from X-ray structures and preexisting knowledge of inhibitors; however, an efficient method to generate Mpro inhibitors, which circumvents such information would be advantageous. As an alternative approach, we show here that DNA-encoded chemistry technology (DEC-Tec) can be used to discover inhibitors of Mpro. An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using Mpro as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of Mpro with low nanomolar Ki values. Furthermore, these compounds demonstrate efficacy against mutant forms of Mpro that have shown resistance to the standard-of-care drug nirmatrelvir. Overall, this work demonstrates that DEC-Tec can efficiently generate novel and potent inhibitors without preliminary chemical or structural information.
Nature Communications
The recent emergence of highly transmissible SARS-CoV-2 variants illustrates the urgent need to b... more The recent emergence of highly transmissible SARS-CoV-2 variants illustrates the urgent need to better understand the molecular details of the virus binding to its host cell and to develop anti-viral strategies. While many studies focused on the role of the angiotensin-converting enzyme 2 receptor in the infection, others suggest the important role of cell attachment factors such as glycans. Here, we use atomic force microscopy to study these early binding events with the focus on the role of sialic acids (SA). We show that SARS-CoV-2 binds specifically to 9-O-acetylated-SA with a moderate affinity, supporting its role as an attachment factor during virus landing to cell host surfaces. For therapeutic purposes and based on this finding, we have designed novel blocking molecules with various topologies and carrying a controlled number of SA residues, enhancing affinity through a multivalent effect. Inhibition assays show that the AcSA-derived glycoclusters are potent inhibitors of ce...
Journal of medicinal chemistry, 2021
Pseudomonas aeruginosa (P.A.) is a human pathogen belonging to the top priorities for the discove... more Pseudomonas aeruginosa (P.A.) is a human pathogen belonging to the top priorities for the discovery of new therapeutic solutions. Its propensity to generate biofilms strongly complicates the treatments required to cure P.A. infections. Herein, we describe the synthesis of a series of novel rotaxanes composed of a central galactosylated pillar[5]arene, a tetrafucosylated dendron, and a tetraguanidinium subunit. Besides the high affinity of the final glycorotaxanes for the two P.A. lectins LecA and LecB, potent inhibition levels of biofilm growth were evidenced, showing that their three subunits work synergistically. An antibiofilm assay using a double ΔlecAΔlecB mutant compared to the wild type demonstrated that the antibiofilm activity of the best glycorotaxane is lectin-mediated. Such antibiofilm potency had rarely been reached in the literature. Importantly, none of the final rotaxanes was bactericidal, showing that their antibiofilm activity does not depend on bacteria killing, w...
Proceedings of the National Academy of Sciences of the United States of America, 2021
Significance SARS-CoV-2 has had a crippling impact on human life globally. Vaccine development ha... more Significance SARS-CoV-2 has had a crippling impact on human life globally. Vaccine development has been used as a first-line strategy for COVID-19 prevention and mitigation; however, small-molecule drugs are still vitally needed to extend treatment options. Traditional screening methods for identifying biologically active small molecules are sluggish and often sample an insufficient number of compounds to identify suitable hits. Here, we applied a screening method known as DNA-encoded chemistry technology (DEC-Tec) to screen billions of compounds against a critical viral protein, Mpro. In rapid fashion, we identified the compound CDD-1713 as a potent and selective Mpro inhibitor. This study illuminates DEC-Tec as a highly expeditious strategy toward generating small molecules against critical targets of infectious agents. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration...
Modulators of microtubule dynamics have received increasing attention because of their potential ... more Modulators of microtubule dynamics have received increasing attention because of their potential to stop cancer growth. Although it belongs to the category of complex protein-protein interactions (PPIs), which are generally considered difficult to modulate through small molecules, the use of microtubule is considered a well-validated target. There are a number of bioactive natural products and related compounds that are currently in use as drugs or in clinical trials as next generation anti-cancer agents. The present review article is focused on two such bioactive natural products, epothilone and halichondrin B, and covers some of the key papers published after 2005 that outline various synthetic approaches to obtain next generation structural analogs as well as the synthesis of hybrid compounds.
European Journal of Organic Chemistry, 2014
Keywords: Natural products / Macrocycles / Mitochondria / Cell death / Diabetes Mitochondria prod... more Keywords: Natural products / Macrocycles / Mitochondria / Cell death / Diabetes Mitochondria produce the majority of cellular energy through the process of oxidative phosphorylation and play a central role in regulating the functionality and survival of eukaryotic cells. Under physiological stress, mitochondrial membrane permeabilization results in the release of apoptogenic material such as cytochrome c in the cytoplasm, which thereby initiates caspase activation and the conse-quent cell death. In our present study, we screened a series of compounds for their ability to inhibit mitochondrial mem-brane permeabilization and to prevent cytochrome c release during the endoplasmic reticulum stress in cultured
Nature Communications
It is assumed that intracellular pathogenic bacteria have to cope with DNA alkylating stress with... more It is assumed that intracellular pathogenic bacteria have to cope with DNA alkylating stress within host cells. Here we use single-cell reporter systems to show that the pathogenBrucella abortusdoes encounter alkylating stress during the first hours of macrophage infection. Genes encoding direct repair and base-excision repair pathways are required byB. abortusto face this stress in vitro and in a mouse infection model. Among these genes,ogtis found to be under the control of the conserved cell-cycle transcription factor GcrA. Our results highlight that the control of DNA repair inB. abortusdisplays distinct features that are not present in model organisms such asEscherichia coli.
Organic Letters
A stereoselective synthesis of a rapamycin fragment is developed and further utilized toward buil... more A stereoselective synthesis of a rapamycin fragment is developed and further utilized toward building a macrocyclic chemical toolbox. The amino alcohol moiety embedded in the 22-membered macrocyclic ring allowed for the addition of a variation in the chiral side chain. The key reactions leading to the synthesis of the rapamycin-derived pyran fragment include the following: (i) Paterson aldol, (ii) stereoselective β-OH carbonyl reduction, and (iii) regio- and stereoselective intramolecular oxy-Michael reaction. The other piece needed for building the macrocyclic diversity was obtained from the coupling of various amino alcohol moieties with S-pipecolic acid.
Introduction 4641 1.1. Going in for Protein−Protein Interactions and Pathways 4641 1.2. Protein−P... more Introduction 4641 1.1. Going in for Protein−Protein Interactions and Pathways 4641 1.2. Protein−Protein Interactions and Small Molecules 4641 2. Case Study 1: Tubulin Polymerization and Natural Product-Derived Small Molecules 4642 3. Case Study 2: p53 and MDM2 Interactions and Small Molecules 4649 3.1. Natural Product Inhibitors of p53−MDM2 Interactions 4650 3.2. β-Hairpin Peptidomimetics 4652 3.3. Terphenyls 4653 3.4. Nutlins 4653 3.5. Benzodiazepines 4654 3.6. Spiro-oxindoles 4656 3.7. Chromenotriazolopyrimidines 4656 3.8. Piperidinones 4657 3.9. Indolo-imidazoles 4658 4. Case Study 3: Modulation of HSP90-Related Protein−Protein Interactions by Natural Products and Related Compounds 4659 4.1. Structure, Conformation, and Functions of HSP 4659 4.2. Hsp90 Inhibitors 4660 5. Case Study 4: Protein−Protein Interactions Centered on the Inhibitors of Apoptosis Proteins (IAPs) and Synthetic Small Molecules 4666 5.1. Overview of Functions of IAPs 4666 5.2. Death Receptor Pathway of Caspase Activation 4667 5.3. Mitochondrial Pathway of Caspase Activation 4667 5.4. Converging Points and Cross-Talk 4667 5.5. Nonpeptidic Small Molecules 4668 5.5.1. TWX Molecules: First Reported Nonpeptide Inhibitor of XIAP (BIR2 domain) 4668 5.
Organic letters, Jan 12, 2015
A practical stereoselective synthesis to obtain the substituted furan ring as the substructure of... more A practical stereoselective synthesis to obtain the substituted furan ring as the substructure of eribulin is developed. An asymmetric syn-aldol and intramolecular oxy-Michael were two key steps in our approach. The functionalized furan derivatives were then utilized further to build the 14- and 12-membered macrocyclic diversity as trans- and cis-fused (C-29 and C-30) compounds. This is the first report of building a chemical toolbox with macrocyclic small molecules having trans- or cis-fused 14- or 12-membered rings containing the substructure of eribulin and its diastereomer.
ABSTRACT Some case studies for small molecule modulators of protein-protein interactions (PPI) ar... more ABSTRACT Some case studies for small molecule modulators of protein-protein interactions (PPI) are reviewed. It has been shown that in general natural products are proven to be highly effective in modulating PPI, and in many cases, this is achieved through the interactions utilizing the allosteric sites. As shown through some specific case studies, the structural information about the PP interface has also been highly useful in designing synthetic compounds. There is a growth in activity in building chemical toolboxes having compounds that are closer to bioactive natural products. This would also challenge the synthetic community to develop new approaches to access a wide variety of natural product-like or natural product inspired scaffolds. One such area that is gaining momentum is to establish methods that allows building the macrocyclic-based chemical toolboxes. Discovery of functional small molecule modulators of PPI demands a close interaction of the synthesis community working closely with other skill sets that are specialized in various aspects of studying these interactions.