Dr. Robert Ridley | Unicaf (original) (raw)
Papers by Dr. Robert Ridley
Journal of Medicinal Chemistry, Sep 25, 1998
ABSTRACT N,N-Bis(7-chloroquinolin-4-yl)heteroalkanediamines 1-11 were synthesized and screened ag... more ABSTRACT N,N-Bis(7-chloroquinolin-4-yl)heteroalkanediamines 1-11 were synthesized and screened against Plasmodium falciparum in vitro and Plasmodium berghei in vivo. These bisquinolines had IC50 values from 1 to 100 nM against P. falciparum in vitro. Six of the 11 bisquinolines were significantly more potent against the chloroquine-resistant W2 clone compared to the chloroquine-sensitive D6 clone. For bisquinolines 1-11 there was no relationship between the length of the bisquinoline heteroalkane bridge and antimalarial activity and no correlation between in vitro and in vivo antimalarial activities. Bisquinolines with alkyl ether and piperazine bridges were substantially more effective than bisquinolines with alkylamine bridges against P. berghei in vivo. Bisquinolines 1-10 were potent inhibitors of hematin polymerization with IC50 values falling in the narrow range of 5-20 microM, and there was a correlation between potency of inhibition of hematin polymerization and inhibition of parasite growth. Compared to alkane-bridged bisquinolines (Vennerstrom et al., 1992), none of these heteroalkane-bridged bisquinolines had sufficient antimalarial activity to warrant further investigation of the series.
Genetics Research, Jun 1, 1988
Current Opinion in Infectious Diseases, Dec 1, 1998
Clinical trials continue to provide evidence for the efficacy of semi-synthetic artemisinin deriv... more Clinical trials continue to provide evidence for the efficacy of semi-synthetic artemisinin derivatives and the novel fixed dose combination therapies Malarone, co-artemether and chlorproguanil-dapsone. Single agents under development include the 8-aminoquinoline etaquine, pyronaridine and azithromycin. Preclinical interest in synthetic endoperoxides and quinoline analogues remains high and a significant is also being made in natural product chemistry. Dihydrofolate reductase remains a molecular drug target of interest, whereas phospholipid metabolism represents a new approach. Genomic information is likely to produce many new drug targets for exploration in the coming decade.
Nature Reviews Microbiology, Nov 1, 2007
A cDNA clone spanning the entire amino acid sequence of the nuclear-encoded uncoupling protein of... more A cDNA clone spanning the entire amino acid sequence of the nuclear-encoded uncoupling protein of rat brown adipose tissue mitochondria has been isolated and sequenced. With the exception of the N-terminal methionine the deduced N-terminus of the newly synthesized uncoupling protein is identical to the N-terminal 30 amino acids of the native uncoupling protein as determined by protein sequencing. This proves that the protein contains no Nterminal mitochondrial targeting prepiece and that a targeting region must reside within the amino acid sequence of the mature protein.
Biochemical Society Transactions, Apr 1, 1991
Over the last decade many malarial antigens have been cloned and sequenced [ 1-31. Initial sequen... more Over the last decade many malarial antigens have been cloned and sequenced [ 1-31. Initial sequences were intriguing as many antigens appeared to contain multiple repeats of peptide subunits which ranged from 3 to 80 amino acids in length. These repeat units can occupy between 2 and 90% of the total protein sequence and occur in proteins ranging from 30 to 300 kDa (Fig. 1). It has been postnlated that the large number of repetitive antigens in malaria, some of which contain cross-reactive epitopes and many of which are immunodominant, may play a significant part in protecting the parasite from the host's immune system [2, 31. Before proceeding with this discussion, however, it is necessary to describe the life cycle of the parasite so that the immune response to malaria may be better understood. The most virulent of the human malaria parasites Plasmodium falciparum, like other members of the genus Plamodium, undergoes a complex life
Infection and Immunity, 1993
Clinical and Diagnostic Laboratory Immunology, 1998
To examine the role of the Plasmodium falciparum Exp-1 blood-stage protein in producing antibodie... more To examine the role of the Plasmodium falciparum Exp-1 blood-stage protein in producing antibodies that cross-react with human T-cell lymphotropic virus type I (HTLV-I) proteins, we studied sera from Indonesian volunteers who seroconverted to malaria after transmigrating to an area where malaria is hyperendemic. Samples from Philippine volunteers, that were used in a prior study that examined malaria antibodies that cross-react with HTLV-I proteins, were also used. Eighty-three percent of the Indonesian transmigrants developed antibodies against the malaria Exp-1 protein by 6 months postmigration. Of these malaria seroconverters, 27% developed false-positive HTLV-I enzyme immunoassay (EIA) immunoreactivity, as indicated by indeterminate HTLV-I Western blot banding patterns. Five of the six Philippine samples tested were HTLV-I EIA false positive and Western blot indeterminate. When a recombinant Exp-1 protein was used in blocking experiments, the HTLV-I Western blot immunoreactivity...
The American Journal of Tropical Medicine and Hygiene, 1996
... Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark: National Institut... more ... Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark: National Institute for Medical Research, Amani Centre, Amani, Tanzania: National ... The thin blood smears were fixed with methanol; blood slides were stained with 10% Giemsa stain (pH 7.2) for ...
Molecular and Cellular Biology, 1991
Merozoite surface antigen MSA-2 of the human parasite Plasmodium falciparum is being considered f... more Merozoite surface antigen MSA-2 of the human parasite Plasmodium falciparum is being considered for the development of a malaria vaccine. The antigen is polymorphic, and specific monoclonal antibodies differentiate five serological variants of MSA-2 among 25 parasite isolates. The variants are grouped into two major serogroups, A and B. Genes encoding two different variants from serogroup A have been sequenced, and their DNA together with deduced amino acid sequences were compared with sequences encoded by other alleles. The comparison shows that the serological classification reflects differences in DNA sequences and deduced primary structure of MSA-2 variants and serogroups. Thus, the overall homologies of DNA and amino acid sequences are over 95% among variants in the same serogroup. In contrast, similarities between the group A variants and a group B variant are only 70 and 64% for DNA and amino acid sequences, respectively. We propose that the MSA-2 protein is encoded by two hi...
Immunology, 2001
To better understand reasons for increased susceptibility to malaria in pregnancy; and the interr... more To better understand reasons for increased susceptibility to malaria in pregnancy; and the interrelationships between maternal malaria, local immune reactions and the development of the fetus, concentrations of soluble interleukin‐10 (IL‐10), cytokine receptors, adhesion molecules, a Plasmodium falciparum protein, glutamate‐rich protein (GLURP) and antibodies to P. falciparum rhoptry‐associated protein‐1 were measured among 105 Gambian women and their neonates. Peripheral blood concentrations of IL‐10, soluble cytokine receptors and soluble adhesion molecules were found to be different from those concentrations measured in the placenta. Markers of inflammatory reactions: IL‐10, sIL‐2R, sIL‐4R, and soluble tumour necrosis factor receptor I (sTNF‐RI) were found in high concentrations in the placenta, indicating that inflammatory reactions take place in the placenta which has been regarded as an immunoprivileged site. Concentrations of soluble vascular cell adhesion molecule‐1 (sVCAM‐1...
The American Journal of Tropical Medicine and Hygiene, 2001
Floxacrine was a promising antimalarial compound that led to the identification of WR 243251. On ... more Floxacrine was a promising antimalarial compound that led to the identification of WR 243251. On the basis of their structures, we suspected that these compounds might be good inhibitors of hematin polymerization. Indeed, WR 243251 was as potent and floxacrine was only 2-fold less potent than chloroquine as inhibitors of this process. However, this hematin polymerization inhibition did not completely account for the increased antimalarial potency of WR 243251 versus chloroquine. The WR 243251 ketone hydrolysis product WR 243246 was without activity against hematin polymerization. These data also confirm that hematin polymerization inhibition can be quite sensitive to small changes in inhibitor structure.
Expert Opinion on Therapeutic Patents, 1998
Page 1. Ridley & Hudson Quinoline antimalarials Quinoline antimalarials Robert G Ridley... more Page 1. Ridley & Hudson Quinoline antimalarials Quinoline antimalarials Robert G Ridley & Alan T Hudson Pharmaceuticals Division, Dept. PRPI-D, F Hoffmann-La Roche, CH-4070 Basel, Switzerland SemaphoR, Sittingbourne ...
Advances in Experimental Medicine and Biology, 1998
During an infection of erythrocytes by the human malarial parasite Plasmodium falciparum, up to 8... more During an infection of erythrocytes by the human malarial parasite Plasmodium falciparum, up to 80% of host cell haemoglobin is degraded to provide amino acids for parasite nutrition.1,2 Two aspartic proteinases, plasmepsin I and plasmepsin II are believed to be responsible for initiating this catabolic process3 and thus are suitable targets for antimalarial chemotherapy. These enzymes have 73% identity to each other and approximately 30%) identity to the five known human aspartic proteinases.
Bulletin of the World Health Organization, 2001
Bulletin of the World Health Organization, Oct 24, 2001
Antimicrobial Agents and Chemotherapy, 1996
We have synthesized several 4-aminoquinolines with shortened side chains that retain activity aga... more We have synthesized several 4-aminoquinolines with shortened side chains that retain activity against chloroquine-resistant isolates of Plasmodium falciparum malaria (W. Hofheinz, C. Jaquet, and S. Jolidon, European patent 94116281.0, June 1995). We report here an assessment of the activities of four selected compounds containing ethyl, propyl, and isopropyl side chains. Reasonable in vitro activity (50% inhibitory concentration, < 100 nM) against chloroquine-resistant P. falciparum strains was consistently observed, and the compounds performed well in a variety of plasmodium berghei animal models. However, some potential drawbacks of these compounds became evident upon in-depth testing. In vitro analysis of more than 70 isolates of P. falciparum and studies with a mouse in vivo model suggested a degree of cross-resistance with chloroquine. In addition, pharmacokinetic analysis demonstrated the formation of N-dealkylated metabolites of these compounds. These metabolites are simil...
shortened side chains retain activity against 4-aminoquinoline analogs of chloroquine with
Journal of Medicinal Chemistry, Sep 25, 1998
ABSTRACT N,N-Bis(7-chloroquinolin-4-yl)heteroalkanediamines 1-11 were synthesized and screened ag... more ABSTRACT N,N-Bis(7-chloroquinolin-4-yl)heteroalkanediamines 1-11 were synthesized and screened against Plasmodium falciparum in vitro and Plasmodium berghei in vivo. These bisquinolines had IC50 values from 1 to 100 nM against P. falciparum in vitro. Six of the 11 bisquinolines were significantly more potent against the chloroquine-resistant W2 clone compared to the chloroquine-sensitive D6 clone. For bisquinolines 1-11 there was no relationship between the length of the bisquinoline heteroalkane bridge and antimalarial activity and no correlation between in vitro and in vivo antimalarial activities. Bisquinolines with alkyl ether and piperazine bridges were substantially more effective than bisquinolines with alkylamine bridges against P. berghei in vivo. Bisquinolines 1-10 were potent inhibitors of hematin polymerization with IC50 values falling in the narrow range of 5-20 microM, and there was a correlation between potency of inhibition of hematin polymerization and inhibition of parasite growth. Compared to alkane-bridged bisquinolines (Vennerstrom et al., 1992), none of these heteroalkane-bridged bisquinolines had sufficient antimalarial activity to warrant further investigation of the series.
Genetics Research, Jun 1, 1988
Current Opinion in Infectious Diseases, Dec 1, 1998
Clinical trials continue to provide evidence for the efficacy of semi-synthetic artemisinin deriv... more Clinical trials continue to provide evidence for the efficacy of semi-synthetic artemisinin derivatives and the novel fixed dose combination therapies Malarone, co-artemether and chlorproguanil-dapsone. Single agents under development include the 8-aminoquinoline etaquine, pyronaridine and azithromycin. Preclinical interest in synthetic endoperoxides and quinoline analogues remains high and a significant is also being made in natural product chemistry. Dihydrofolate reductase remains a molecular drug target of interest, whereas phospholipid metabolism represents a new approach. Genomic information is likely to produce many new drug targets for exploration in the coming decade.
Nature Reviews Microbiology, Nov 1, 2007
A cDNA clone spanning the entire amino acid sequence of the nuclear-encoded uncoupling protein of... more A cDNA clone spanning the entire amino acid sequence of the nuclear-encoded uncoupling protein of rat brown adipose tissue mitochondria has been isolated and sequenced. With the exception of the N-terminal methionine the deduced N-terminus of the newly synthesized uncoupling protein is identical to the N-terminal 30 amino acids of the native uncoupling protein as determined by protein sequencing. This proves that the protein contains no Nterminal mitochondrial targeting prepiece and that a targeting region must reside within the amino acid sequence of the mature protein.
Biochemical Society Transactions, Apr 1, 1991
Over the last decade many malarial antigens have been cloned and sequenced [ 1-31. Initial sequen... more Over the last decade many malarial antigens have been cloned and sequenced [ 1-31. Initial sequences were intriguing as many antigens appeared to contain multiple repeats of peptide subunits which ranged from 3 to 80 amino acids in length. These repeat units can occupy between 2 and 90% of the total protein sequence and occur in proteins ranging from 30 to 300 kDa (Fig. 1). It has been postnlated that the large number of repetitive antigens in malaria, some of which contain cross-reactive epitopes and many of which are immunodominant, may play a significant part in protecting the parasite from the host's immune system [2, 31. Before proceeding with this discussion, however, it is necessary to describe the life cycle of the parasite so that the immune response to malaria may be better understood. The most virulent of the human malaria parasites Plasmodium falciparum, like other members of the genus Plamodium, undergoes a complex life
Infection and Immunity, 1993
Clinical and Diagnostic Laboratory Immunology, 1998
To examine the role of the Plasmodium falciparum Exp-1 blood-stage protein in producing antibodie... more To examine the role of the Plasmodium falciparum Exp-1 blood-stage protein in producing antibodies that cross-react with human T-cell lymphotropic virus type I (HTLV-I) proteins, we studied sera from Indonesian volunteers who seroconverted to malaria after transmigrating to an area where malaria is hyperendemic. Samples from Philippine volunteers, that were used in a prior study that examined malaria antibodies that cross-react with HTLV-I proteins, were also used. Eighty-three percent of the Indonesian transmigrants developed antibodies against the malaria Exp-1 protein by 6 months postmigration. Of these malaria seroconverters, 27% developed false-positive HTLV-I enzyme immunoassay (EIA) immunoreactivity, as indicated by indeterminate HTLV-I Western blot banding patterns. Five of the six Philippine samples tested were HTLV-I EIA false positive and Western blot indeterminate. When a recombinant Exp-1 protein was used in blocking experiments, the HTLV-I Western blot immunoreactivity...
The American Journal of Tropical Medicine and Hygiene, 1996
... Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark: National Institut... more ... Microbiology and Immunology, University of Copenhagen, Copenhagen, Denmark: National Institute for Medical Research, Amani Centre, Amani, Tanzania: National ... The thin blood smears were fixed with methanol; blood slides were stained with 10% Giemsa stain (pH 7.2) for ...
Molecular and Cellular Biology, 1991
Merozoite surface antigen MSA-2 of the human parasite Plasmodium falciparum is being considered f... more Merozoite surface antigen MSA-2 of the human parasite Plasmodium falciparum is being considered for the development of a malaria vaccine. The antigen is polymorphic, and specific monoclonal antibodies differentiate five serological variants of MSA-2 among 25 parasite isolates. The variants are grouped into two major serogroups, A and B. Genes encoding two different variants from serogroup A have been sequenced, and their DNA together with deduced amino acid sequences were compared with sequences encoded by other alleles. The comparison shows that the serological classification reflects differences in DNA sequences and deduced primary structure of MSA-2 variants and serogroups. Thus, the overall homologies of DNA and amino acid sequences are over 95% among variants in the same serogroup. In contrast, similarities between the group A variants and a group B variant are only 70 and 64% for DNA and amino acid sequences, respectively. We propose that the MSA-2 protein is encoded by two hi...
Immunology, 2001
To better understand reasons for increased susceptibility to malaria in pregnancy; and the interr... more To better understand reasons for increased susceptibility to malaria in pregnancy; and the interrelationships between maternal malaria, local immune reactions and the development of the fetus, concentrations of soluble interleukin‐10 (IL‐10), cytokine receptors, adhesion molecules, a Plasmodium falciparum protein, glutamate‐rich protein (GLURP) and antibodies to P. falciparum rhoptry‐associated protein‐1 were measured among 105 Gambian women and their neonates. Peripheral blood concentrations of IL‐10, soluble cytokine receptors and soluble adhesion molecules were found to be different from those concentrations measured in the placenta. Markers of inflammatory reactions: IL‐10, sIL‐2R, sIL‐4R, and soluble tumour necrosis factor receptor I (sTNF‐RI) were found in high concentrations in the placenta, indicating that inflammatory reactions take place in the placenta which has been regarded as an immunoprivileged site. Concentrations of soluble vascular cell adhesion molecule‐1 (sVCAM‐1...
The American Journal of Tropical Medicine and Hygiene, 2001
Floxacrine was a promising antimalarial compound that led to the identification of WR 243251. On ... more Floxacrine was a promising antimalarial compound that led to the identification of WR 243251. On the basis of their structures, we suspected that these compounds might be good inhibitors of hematin polymerization. Indeed, WR 243251 was as potent and floxacrine was only 2-fold less potent than chloroquine as inhibitors of this process. However, this hematin polymerization inhibition did not completely account for the increased antimalarial potency of WR 243251 versus chloroquine. The WR 243251 ketone hydrolysis product WR 243246 was without activity against hematin polymerization. These data also confirm that hematin polymerization inhibition can be quite sensitive to small changes in inhibitor structure.
Expert Opinion on Therapeutic Patents, 1998
Page 1. Ridley & Hudson Quinoline antimalarials Quinoline antimalarials Robert G Ridley... more Page 1. Ridley & Hudson Quinoline antimalarials Quinoline antimalarials Robert G Ridley & Alan T Hudson Pharmaceuticals Division, Dept. PRPI-D, F Hoffmann-La Roche, CH-4070 Basel, Switzerland SemaphoR, Sittingbourne ...
Advances in Experimental Medicine and Biology, 1998
During an infection of erythrocytes by the human malarial parasite Plasmodium falciparum, up to 8... more During an infection of erythrocytes by the human malarial parasite Plasmodium falciparum, up to 80% of host cell haemoglobin is degraded to provide amino acids for parasite nutrition.1,2 Two aspartic proteinases, plasmepsin I and plasmepsin II are believed to be responsible for initiating this catabolic process3 and thus are suitable targets for antimalarial chemotherapy. These enzymes have 73% identity to each other and approximately 30%) identity to the five known human aspartic proteinases.
Bulletin of the World Health Organization, 2001
Bulletin of the World Health Organization, Oct 24, 2001
Antimicrobial Agents and Chemotherapy, 1996
We have synthesized several 4-aminoquinolines with shortened side chains that retain activity aga... more We have synthesized several 4-aminoquinolines with shortened side chains that retain activity against chloroquine-resistant isolates of Plasmodium falciparum malaria (W. Hofheinz, C. Jaquet, and S. Jolidon, European patent 94116281.0, June 1995). We report here an assessment of the activities of four selected compounds containing ethyl, propyl, and isopropyl side chains. Reasonable in vitro activity (50% inhibitory concentration, < 100 nM) against chloroquine-resistant P. falciparum strains was consistently observed, and the compounds performed well in a variety of plasmodium berghei animal models. However, some potential drawbacks of these compounds became evident upon in-depth testing. In vitro analysis of more than 70 isolates of P. falciparum and studies with a mouse in vivo model suggested a degree of cross-resistance with chloroquine. In addition, pharmacokinetic analysis demonstrated the formation of N-dealkylated metabolites of these compounds. These metabolites are simil...
shortened side chains retain activity against 4-aminoquinoline analogs of chloroquine with