New Aza-Dipeptide Analogues as Potent and Orally Absorbed HIV-1 Protease Inhibitors:  Candidates for Clinical Development

Bold, Guido; Fässler, Alexander; Capraro, Hans‐Georg; Cozens, Robert; Klimkait, Thomas; Lazdins, Janis; Mestan, Jürgen; Poncioni, Bernard; Rösel, Johannes; Stover, David R.; Tintelnot‐Blomley, Marina; Acemoglu, Figan; Beck, Werner; Boss, Eugen; Eschbach, Martin; Hürlimann, Thomas; Masso, Elvira; Roussel, Serge; Ucci-Stoll, Katharina; Wyss, Dominique; Lang, Marc

doi:10.1021/jm970873c

Cited by 190 publications

(114 citation statements)

References 22 publications

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“…The in vivo activity of the HIV-1 aspartyl protease inhibitors saquinavir, ritonavir, ritonavir-saquinavir, and ritonavir-lopinavir was determined in a nonlethal murine malaria model. Female C57BL/6J mice were infected with 10 5 P. chabaudi AS-parasitized erythrocytes, and the antiretroviral drugs, or vehicle control, were administered orally twice daily for 8 consecutive days, starting 24 h postinfection. Drug doses were selected based on plasma concentrations achieved in mice (Table 2) and were as follows: 10 mg/kg ritonavir, 10 mg/kg ritonavir-40 mg/kg lopinavir, 10 mg/kg each ritonavir and saquinavir, and 10 mg/kg saquinavir.…”

Section: Resultsmentioning

confidence: 99%

Potencies of Human Immunodeficiency Virus Protease Inhibitors In Vitro againstPlasmodium falciparumand In Vivo against Murine Malaria

Andrews

Fairlie

Madala

et al. 2006

Antimicrob Agents Chemother

126

128

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Parasite resistance to antimalarial drugs is a serious threat to human health, and novel agents that act on enzymes essential for parasite metabolism, such as proteases, are attractive targets for drug development. Recent studies have shown that clinically utilized human immunodeficiency virus (HIV) protease inhibitors can inhibit the in vitro growth of Plasmodium falciparum at or below concentrations found in human plasma after oral drug administration. The most potent in vitro antimalarial effects have been obtained for parasites treated with saquinavir, ritonavir, or lopinavir, findings confirmed in this study for a genetically distinct P. falciparum line (3D7). To investigate the potential in vivo activity of antiretroviral protease inhibitors (ARPIs) against malaria, we examined the effect of ARPI combinations in a murine model of malaria. In mice infected with Plasmodium chabaudi AS and treated orally with ritonavir-saquinavir or ritonavir-lopinavir, a delay in patency and a significant attenuation of parasitemia were observed. Using modeling and ligand docking studies we examined putative ligand binding sites of ARPIs in aspartyl proteases of P. falciparum (plasmepsins II and IV) and P. chabaudi (plasmepsin) and found that these in silico analyses support the antimalarial activity hypothesized to be mediated through inhibition of these enzymes. In addition, in vitro enzyme assays demonstrated that P. falciparum plasmepsins II and IV are both inhibited by the ARPIs saquinavir, ritonavir, and lopinavir. The combined results suggest that ARPIs have useful antimalarial activity that may be especially relevant in geographical regions where HIV and P. falciparum infections are both endemic.

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Section: Resultsmentioning

confidence: 99%

Potencies of Human Immunodeficiency Virus Protease Inhibitors In Vitro againstPlasmodium falciparumand In Vivo against Murine Malaria

Andrews

Fairlie

Madala

et al. 2006

Antimicrob Agents Chemother

126

128

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“…Related phenyl vinyl sulfones also inhibit cruzain, a cysteine protease of Trypanosoma cruzi (31,32,35), and one of these compounds is currently undergoing preclinical studies for the treatment of Chagas' disease (34). While the clinical use of peptidyl protease inhibitors is potentially problematic due to limited bioavailability or poor pharmacokinetics, there are numerous recent reports of peptidyl inhibitors of renin (17), thrombin (11), leukocyte elastase (42), neutrophil elastase (8), and human immunodeficiency virus type 1 protease (2,16,40) that are biologically active after oral administration. Considering these data, the reported in vivo efficacy of an orally administered vinyl sulfone against murine malaria (22), and our demonstration here of marked antimalarial potency, additional evaluation of vinyl sulfonyl derivatives as potential antimalarial cysteine protease inhibitors seems appropriate.…”

Section: Discussionmentioning

confidence: 99%

Structure-Activity Relationships for Inhibition of Cysteine Protease Activity and Development of Plasmodium falciparum by Peptidyl Vinyl Sulfones

Shenai

Lee

Álvarez‐Hernández

et al. 2003

Antimicrob Agents Chemother

160

148

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The Plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3 appear to be required for hemoglobin hydrolysis by intraerythrocytic malaria parasites. Previous studies showed that peptidyl vinyl sulfone inhibitors of falcipain-2 blocked the development of P. falciparum in culture and exerted antimalarial effects in vivo. We now report the structure-activity relationships for inhibition of falcipain-2, falcipain-3, and parasite development by 39 new vinyl sulfone, vinyl sulfonate ester, and vinyl sulfonamide cysteine protease inhibitors. Levels of inhibition of falcipain-2 and falcipain-3 were generally similar, and many potent compounds were identified. Optimal antimalarial compounds, which inhibited P. falciparum development at low nanomolar concentrations, were phenyl vinyl sulfones, vinyl sulfonate esters, and vinyl sulfonamides with P 2 leucine moieties. Our results identify independent structural correlates of falcipain inhibition and antiparasitic activity and suggest that peptidyl vinyl sulfones have promise as antimalarial agents.Malaria is one of the most important infectious diseases in the world. Plasmodium falciparum, the most virulent human malaria parasite, is estimated to cause over 300 million new cases and 1 million deaths annually (33). Further complicating this grim scenario is the emergence of the widespread resistance of P. falciparum to available antimalarial drugs (25). New drugs to combat malaria are urgently needed.Among potential new targets for antimalarial chemotherapy are enzymes that mediate hemoglobin hydrolysis. Intraerythrocytic P. falciparum trophozoites derive amino acids for protein synthesis from the hydrolysis of host cell hemoglobin in an acidic food vacuole (12,20,27). Proteases that hydrolyze hemoglobin in the food vacuole include members of the aspartic protease (1), cysteine protease (38, 39), and metalloprotease (9) families. Cysteine protease inhibitors arrested the erythrocytic life cycle of P. falciparum (26). Examination of inhibitortreated parasites revealed abnormally swollen food vacuoles filled with undigested hemoglobin, indicating that the block in parasite development was due to the inhibition of hemoglobin hydrolysis (26).P. falciparum contains three fairly typical papain family cysteine proteases, known as falcipains (28,38,39). Falcipain-2 and falcipain-3 appear to be the principal cysteine protease hemoglobinases (38, 39). Both of these proteases localize to vacuolar parasite fractions and readily hydrolyze hemoglobin under physiological reducing conditions at acidic pHs (37). Falcipain-2 is considerably more active against small peptide substrates, but the specificities of the two proteases are similar; both enzymes display a strong preference for leucine at the P 2 position (38, 39). The role of falcipain-1 in hemoglobin hydrolysis is unknown.In earlier studies, peptidyl vinyl sulfones inhibited falcipain-2 activity and parasite development at nanomolar concentrations and were active in vivo against murine malaria (22,29,30). We have now init...

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“…This led to the discovery of a series of molecules that showed similar antiviral activity as SQV and had excellent oral bioavailability. After further characterization, ATV was selected from this group and advanced through clinical trials [110].…”

Section: Drug Optimizationmentioning

confidence: 99%

TheFDAApprovedHIV‐1 Protease Inhibitors for Treatment ofHIV/AIDS

Ghosh

Anderson

Mitsuya

2010

Burger's Medicinal Chemistry and Drug Discovery

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Over the past two decades, HIV protease inhibitors have helped revolutionize the treatment of HIV/AIDS transforming this deadly ailment into a more manageable chronic infection. Due to intensive research in the area, a variety of protease inhibitors are now commercially available each of which possesses distinct characteristics and a unique tale of discovery. This manuscript reviews the design and development of the 10 currently available protease inhibitors saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir, and darunavir. Special attention is given to the research efforts leading to their discovery and the successes and limitations of these drugs in the clinics. A brief review of the biology associated with the HIV‐1 protease target is provided in addition to a discussion of novel drug candidates currently under investigation.

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New Aza-Dipeptide Analogues as Potent and Orally Absorbed HIV-1 Protease Inhibitors: Candidates for Clinical Development

Cited by 190 publications

References 22 publications

Potencies of Human Immunodeficiency Virus Protease Inhibitors In Vitro againstPlasmodium falciparumand In Vivo against Murine Malaria

Potencies of Human Immunodeficiency Virus Protease Inhibitors In Vitro againstPlasmodium falciparumand In Vivo against Murine Malaria

Structure-Activity Relationships for Inhibition of Cysteine Protease Activity and Development of Plasmodium falciparum by Peptidyl Vinyl Sulfones

TheFDAApprovedHIV‐1 Protease Inhibitors for Treatment ofHIV/AIDS

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