l-685458 and Disease-Models--Animal

Topics: Amyloid Precursor Protein Secretases; Animals; Asthma; Carbamates; Dipeptides; Disease Models, Animal; Drug Evaluation, Preclinical; Lung; Male; Mice, Inbred C57BL; Obesity; Random Allocation; Receptors, Notch; Signal Transduction; Th17 Cells

γ-secretase inhibitors (GSI) are drugs developed to decrease amyloid-β peptide (Aβ) production by inhibiting intramembranous cleavage of β-amyloid protein precursor (βAPP). However, a large phase 3 trial of semagacestat, a potential non-transition state analog (non-TSA) GSI, in patients with Alzheimer's disease (AD) was terminated due to unexpected aggravation of cognitive deficits and side effects. Here, we show that some semagacestat effects are clearly different from a phenotype caused by a loss of function of presenilins, core proteins in the γ-secretase complex. Semagacestat increases intracellular byproduct peptides, produced along with Aβ through serial γ-cleavage of βAPP, as well as intracellular long Aβ species, in cell-based and in vivo studies of AD model mice. Other potential non-TSA GSIs, but not L685,458, a TSA GSI, have similar effects. Furthermore, semagacestat inhibits release of de novo intramembranous γ-byproducts to the soluble space. Thus, semagacestat is a pseudo-GSI, and therefore, the semagacestat clinical trial did not truly test the Aβ hypothesis.

Topics: Alanine; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Azepines; Carbamates; Cell Differentiation; Clinical Trials as Topic; Dipeptides; Disease Models, Animal; Drug Administration Schedule; Enzyme Inhibitors; Gene Expression Regulation; HEK293 Cells; Humans; Induced Pluripotent Stem Cells; Mice; Neurons

Recently we have shown that the highly conserved herpes simplex virus glycoprotein K (gK) binds to signal peptide peptidase (SPP), also known as minor histocompatibility antigen H13. In this study we have demonstrated for the first time that inhibitors of SPP, such as L685,458, (Z-LL)2 ketone, aspirin, ibuprofen and DAPT, significantly reduced HSV-1 replication in tissue culture. Inhibition of SPP activity via (Z-LL)2 ketone significantly reduced viral transcripts in the nucleus of infected cells. Finally, when administered during primary infection, (Z-LL)2 ketone inhibitor reduced HSV-1 replication in the eyes of ocularly infected mice. Thus, blocking SPP activity may represent a clinically effective and expedient approach to the reduction of viral replication and the resulting pathology.

Topics: Animals; Aspartic Acid Endopeptidases; Aspirin; Carbamates; Cell Fractionation; Cells, Cultured; Dipeptides; Disease Models, Animal; DNA, Viral; Enzyme Inhibitors; Female; Gene Expression Regulation, Viral; Herpesvirus 1, Human; Ibuprofen; Keratitis, Herpetic; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Ophthalmic Solutions; Rabbits; Real-Time Polymerase Chain Reaction; RNA, Messenger; Skin; Virus Replication

Transgenic models of Alzheimer's disease (AD) have made significant contributions to our understanding of AD pathogenesis, and are useful tools in the development of potential therapeutics. The fruit fly, Drosophila melanogaster, provides a genetically tractable, powerful system to study the biochemical, genetic, environmental, and behavioral aspects of complex human diseases, including AD. In an effort to model AD, we over-expressed human APP and BACE genes in the Drosophila central nervous system. Biochemical, neuroanatomical, and behavioral analyses indicate that these flies exhibit aspects of clinical AD neuropathology and symptomology. These include the generation of Aβ(40) and Aβ(42), the presence of amyloid aggregates, dramatic neuroanatomical changes, defects in motor reflex behavior, and defects in memory. In addition, these flies exhibit external morphological abnormalities. Treatment with a γ-secretase inhibitor suppressed these phenotypes. Further, all of these phenotypes are present within the first few days of adult fly life. Taken together these data demonstrate that this transgenic AD model can serve as a powerful tool for the identification of AD therapeutic interventions.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Behavior, Animal; Brain; Carbamates; Cognition; Dipeptides; Disease Models, Animal; Drosophila melanogaster; Drug Evaluation, Preclinical; Female; Gene Expression Regulation, Enzymologic; Humans; Male; Motor Activity; Phenotype; Protease Inhibitors; Reflex; Time Factors

Human papillomaviruses (HPV) are common sexually transmitted pathogens that predispose women to cervical and other anogenital cancers. HPV vaccines can prevent infection by some but not other sexually transmitted HPVs but are too costly for use in much of the world at greatest risk to HPV-associated cancers. Microbicides provide an inexpensive alternative to vaccines. In a high throughput screen, drugs that inhibit the cellular protein complex known as gamma secretase were identified as potential HPV microbicides. gamma Secretase inhibitors (GSIs) inhibited the infectivity of HPV pseudoviruses both in human keratinocytes and in mouse cells, with IC(50) values in the picomolar to the nanomolar range. Using a mouse model, we observed that a GSI could inhibit HPV infection to the same degree as its effectiveness in inhibiting gamma secretase activity in vivo. We conclude that gamma secretase activity is required for HPV infection and that GSIs are effective microbicides against anogenital HPVs.

Topics: Amyloid Precursor Protein Secretases; Animals; Anti-Infective Agents; Carbamates; Cell Line; Cells, Cultured; Dipeptides; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Genital Diseases, Female; Human papillomavirus 16; Humans; Keratinocytes; Mice; Papillomavirus Infections; Treatment Outcome