ABSTRACT
The human enzyme deoxyhypusine synthase (DHS) is an important host cell factor that participates in the post-translational hypusine modification of eukaryotic initiation factor 5A (eIF-5A). Hypusine-modified eIF-5A plays a role in a number of diseases, including HIV infection/AIDS. Thus, DHS represents a novel and attractive drug target. So far, four crystal structures are available, and various substances have been tested for inhibition of human DHS. Among these inhibitors, N-1-guanyl-1,7-diaminoheptane (GC7) has been co-crystallized in the active site of DHS. However, despite its potency, GC7 is not selective enough to be used in drug applications. Therefore, new compounds that target DHS are needed. Herein we report the in silico design, chemical synthesis, and biological evaluation of new DHS inhibitors. One of these inhibitors showed dose-dependent inhibition of DHS in vitro, as well as suppression of HIV replication in cell cultures. Furthermore, the compound exhibited no cytotoxic effects at active concentrations. Thus, this designed compound demonstrated proof of principle and represents a promising starting point for the development of new drug candidates to specifically interfere with DHS activity.
Subject(s)
Computer Simulation , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , HIV-1/drug effects , Oxidoreductases Acting on CH-NH Group Donors/antagonists & inhibitors , Virus Replication/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , HIV-1/growth & development , Humans , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Oxidoreductases Acting on CH-NH Group Donors/metabolism , Structure-Activity RelationshipABSTRACT
Smooth muscle sarcomas involving blood vessels, leiomyosarcomas, are rare, making up less than 2% of all leiomyosarcomas. Leiomyosarcoma of the saphenous vein is even more uncommon, with nearly all cases reported occurring in the thigh. This article reviews leiomyosarcoma of blood vessels and reports on a 62-year-old woman with an extremely rare case of a leiomyosarcoma of the distal portion of the greater saphenous at the ankle.
