ABSTRACT
In a continuing study of potent anti-HIV agents, seventeen 28,30-disubstituted betulinic acid (BA, 1) derivatives and seven novel 3,28-disubstituted BA analogues were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, compound 21 showed an improved solubility and equal anti-HIV potency (EC(50) = 0.09 microM) when compared to HIV entry inhibitors 3b (IC9564, (3R,4S)-N'-[N-[3beta-hydroxy-lup-20(29)-en-28-oyl]-8-aminooctanoyl]-4-amino-3-hydroxy-6-methylheptanoic acid) and 4 (A43-D, [[N-[3beta-O-(3',3'-dimethylsuccinyl)-lup-20(29)-en-28-oyl]-7-aminoheptyl]carbamoyl]methane). Using a cyclic secondary amine to form the C-28 amide bond increased the metabolic stability of the derivatives significantly in pooled human liver microsomes. The most potent compounds 47 and 48 displayed potent anti-HIV activity with EC(50) values of 0.007 and 0.006 microM, respectively. These results are slightly better than that of bevirimat (2, 3',3'-dimethylsuccinylbetulinic acid), which is currently in phase IIb clinical trials. Compounds 47 and 48 should serve as attractive promising leads to develop next generation, metabolically stable, 3,28-disubstituted bifunctional HIV-1 inhibitors as clinical trials candidates.
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Triterpenes/chemistry , Anti-HIV Agents/metabolism , Drug Design , Drug Stability , Humans , Inhibitory Concentration 50 , Microsomes, Liver/metabolism , Pentacyclic Triterpenes , Solubility , Structure-Activity Relationship , Triterpenes/metabolism , Triterpenes/pharmacology , Betulinic AcidABSTRACT
3-O-(3',3'-dimethylsuccinyl) betulinic acid, also termed PA-457 or DSB, is a novel HIV-1 inhibitor that blocks virus maturation by disrupting cleavage of the capsid precursor, CA-SP1. To better define the molecular target for PA-457, we prepared a panel of mutant viruses with point deletions spanning the CA-SP1 cleavage domain and characterized each of these viruses for PA-457 sensitivity. Our results indicate that amino acid residues in the N-terminal half of SP1 serve as determinants of PA-457 activity, while residues in the C-terminal half of SP1 were not involved in compound activity. These findings support and extend previous observations that PA-457 is a specific inhibitor of CA-SP1 cleavage and identify the CA-SP1 domain as the primary viral determinant for this novel inhibitor of HIV-1 replication.
Subject(s)
Anti-HIV Agents/pharmacology , HIV-1/drug effects , HIV-1/physiology , Succinates/pharmacology , Triterpenes/pharmacology , Amino Acid Sequence , Capsid Proteins/chemistry , Capsid Proteins/genetics , Capsid Proteins/metabolism , Gene Products, gag/chemistry , Gene Products, gag/genetics , Gene Products, gag/metabolism , HIV-1/genetics , Humans , Jurkat Cells , Microbial Sensitivity Tests/methods , Point Mutation , Protein Precursors/chemistry , Protein Precursors/genetics , Protein Precursors/metabolism , Virus Replication/drug effectsABSTRACT
While it has been established that peptides modeling the C-helical region of human immunodeficiency virus type 1 gp41 are potent in vivo inhibitors of virus replication, their mechanism of action has yet to be determined. It has been proposed, but never directly demonstrated, that these peptides block virus entry by interacting with gp41 to disrupt the formation or function of a six-helix bundle structure. Using a six-helix bundle-specific monoclonal antibody with isolate-restricted Env reactivity, we provide the first direct evidence that, in receptor-activated viral Env, C-peptide entry inhibitors bind to the gp41 N-helical coiled-coil to form a peptide/protein hybrid structure and, in doing so, disrupt native six-helix bundle formation.
Subject(s)
C-Peptide/pharmacology , HIV Envelope Protein gp41/metabolism , HIV-1/physiology , Membrane Fusion/drug effects , Amino Acid Sequence , C-Peptide/metabolism , HIV Envelope Protein gp41/chemistry , Molecular Sequence Data , Sequence Homology, Amino AcidABSTRACT
Most college and university campuses in the United States and much of the developed world today maintain one, two, or several learning management systems (LMSs), which are courseware products that provide students and faculty with Web-based tools to manage course-related applications. Since the mid-1990s, two predominant models of Web courseware management systems have emerged: commercial and noncommercial. Some of the commercial products available today were created in academia as noncommercial but have since become commercially encumbered. Other products remain noncommercial but are struggling to survive in a world of fierce commercial competition. This article argues for an ethics of pedagogy in higher education that would be based on the guiding assumptions of the non-proprietary, peer-to-peer, open-source software movement.
