POTENCY COMPARISON OF PEPTIDOMIMETIC INHIBITORS AGAINST HIV-1 AND HIV-2 PROTEINASES: DESIGN OF EQUIPOTENT LEAD COMPOUNDS
作者： Jan Weber , Pavel Majer , Jaroslav Litera , Jan Urban , Milan Souček
关键词: Peptidomimetic 、 Orders of magnitude (mass) 、 Scissile bond 、 Statine 、 Amide 、 Polyproteins 、 Chemistry 、 Glutamic acid 、 Stereochemistry 、 Isostere
摘要: Abstract HIV-1 and HIV-2 proteinases (PR) are responsible for the processing of viral polyproteins, a step that is crucial formation infectious virus particles. PR represents one most important targets antiviral chemotherapy. Inhibitors usually exhibit 10- to 100-fold weaker affinity PR. In order design subnanomolar inhibitors both PRs, we prepared series compounds varying in type scissile bond replacement as well P1, P1′, P2′ side chains. While containing reduced amide, hydroxyethylamine statine isosteres had K i values range 10 −10 –10 −9 m against PR; their activities were several orders magnitude lower. Glutamic acid was identified be optimal residue PRs. shown more sensitive Glu→Gln replacement. Using this data set able prepare hydroxyethylene isostere equipotent
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