Design of inhibitors against HIV, HTLV-I, and Plasmodium falciparum aspartic proteases
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Hamdy M. Abdel-Rahman
Abstract
Aspartic proteases have emerged as targets for substrate-based inhibitor design due to their vital roles in the life cycles of the organisms that cause AIDS, malaria, leukemia, and other infectious diseases. Based on the concept of mimicking the substrate transition-state, we designed and synthesized a novel class of aspartic protease inhibitors containing the hydroxymethylcarbonyl (HMC) isostere. An unnatural amino acid, allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid], was incorporated at the P1 site in a series of peptidomimetic compounds that mimic the natural substrates of the HIV, HTLV-I, and malarial aspartic proteases. From extensive structure-activity relationship studies, we were able to identify a series of highly potent peptidomimetic inhibitors of HIV protease. One highly potent inhibitor of the malarial aspartic protease (plasmepsin II) was identified. Finally, a promising lead compound against the HTLV-I protease was identified.
References
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© Walter de Gruyter
Artikel in diesem Heft
- Hiroshi Maeda – 40 years of research
- Activation of the kallikrein-kinin system and release of new kinins through alternative cleavage of kininogens by microbial and human cell proteinases
- Molecular mechanism for activation and regulation of matrix metalloproteinases during bacterial infections and respiratory inflammation
- Role of bacterial proteases in pseudomonal and serratial keratitis
- Cysteine cathepsins in human cancer
- Secretory leukoprotease inhibitor and pulmonary surfactant serve as principal defenses against influenza A virus infection in the airway and chemical agents up-regulating their levels may have therapeutic potential
- Design of inhibitors against HIV, HTLV-I, and Plasmodium falciparum aspartic proteases
- Roles of Arg- and Lys-gingipains in coaggregation of Porphyromonas gingivalis: identification of its responsible molecules in translation products of rgpA, kgp, and hagA genes
- Coordinate expression of the Porphyromonas gingivalis lysine-specific gingipain proteinase, Kgp, arginine-specific gingipain proteinase, RgpA, and the heme/hemoglobin receptor, HmuR
- Genetic characterization of staphopain genes in Staphylococcus aureus
- Visualisation of tissue kallikrein, kininogen and kinin receptors in human skin following trauma and in dermal diseases
- Reduction of myocardial infarction by calpain inhibitors A-705239 and A-705253 in isolated perfused rabbit hearts
- A proteinase inhibitor from Caesalpinia echinata (pau-brasil) seeds for plasma kallikrein, plasmin and factor XIIa
- Plasma prekallikrein/kallikrein processing by lysosomal cysteine proteases
- Characteristics of the caspase-like catalytic domain of human paracaspase
- mRNA expression analysis of a variety of apoptosis-related genes, including the novel gene of the BCL2-family, BCL2L12, in HL-60 leukemia cells after treatment with carboplatin and doxorubicin
- Thermoplasma acidophilum TAA43 is an archaeal member of the eukaryotic meiotic branch of AAA ATPases
- Lipopolysaccharide binding of an exchangeable apolipoprotein, apolipophorin III, from Galleria mellonella
Artikel in diesem Heft
- Hiroshi Maeda – 40 years of research
- Activation of the kallikrein-kinin system and release of new kinins through alternative cleavage of kininogens by microbial and human cell proteinases
- Molecular mechanism for activation and regulation of matrix metalloproteinases during bacterial infections and respiratory inflammation
- Role of bacterial proteases in pseudomonal and serratial keratitis
- Cysteine cathepsins in human cancer
- Secretory leukoprotease inhibitor and pulmonary surfactant serve as principal defenses against influenza A virus infection in the airway and chemical agents up-regulating their levels may have therapeutic potential
- Design of inhibitors against HIV, HTLV-I, and Plasmodium falciparum aspartic proteases
- Roles of Arg- and Lys-gingipains in coaggregation of Porphyromonas gingivalis: identification of its responsible molecules in translation products of rgpA, kgp, and hagA genes
- Coordinate expression of the Porphyromonas gingivalis lysine-specific gingipain proteinase, Kgp, arginine-specific gingipain proteinase, RgpA, and the heme/hemoglobin receptor, HmuR
- Genetic characterization of staphopain genes in Staphylococcus aureus
- Visualisation of tissue kallikrein, kininogen and kinin receptors in human skin following trauma and in dermal diseases
- Reduction of myocardial infarction by calpain inhibitors A-705239 and A-705253 in isolated perfused rabbit hearts
- A proteinase inhibitor from Caesalpinia echinata (pau-brasil) seeds for plasma kallikrein, plasmin and factor XIIa
- Plasma prekallikrein/kallikrein processing by lysosomal cysteine proteases
- Characteristics of the caspase-like catalytic domain of human paracaspase
- mRNA expression analysis of a variety of apoptosis-related genes, including the novel gene of the BCL2-family, BCL2L12, in HL-60 leukemia cells after treatment with carboplatin and doxorubicin
- Thermoplasma acidophilum TAA43 is an archaeal member of the eukaryotic meiotic branch of AAA ATPases
- Lipopolysaccharide binding of an exchangeable apolipoprotein, apolipophorin III, from Galleria mellonella