3AID

A NEW CLASS OF HIV-1 PROTEASE INHIBITOR: THE CRYSTALLOGRAPHIC STRUCTURE, INHIBITION AND CHEMICAL SYNTHESIS OF AN AMINIMIDE PEPTIDE ISOSTERE

3AID の概要

• エントリーDOI: 10.2210/pdb3aid/pdb
• 分子名称: HUMAN IMMUNODEFICIENCY VIRUS PROTEASE, BENZOYLAMINO-BENZYL-METHYL-[2-HYDROXY-3-[1-METHYL-ETHYL-OXY-N-FORMAMIDYL]-4-PHENYL-BUTYL]-AMMONIUM (3 entities in total)
• 機能のキーワード: aspartyl protease, protease, hiv, peptide isostere inhibitor, drug design
• 由来する生物種: Human immunodeficiency virus 1
• 細胞内の位置: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P03369
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22108.17

構造登録者

Rutenber, E.E.,Stroud, R.M. (登録日: 1997-05-15, 公開日: 1997-09-17, 最終更新日: 2024-05-22)

主引用文献

Rutenber, E.E.,McPhee, F.,Kaplan, A.P.,Gallion, S.L.,Hogan Jr., J.C.,Craik, C.S.,Stroud, R.M.
A new class of HIV-1 protease inhibitor: the crystallographic structure, inhibition and chemical synthesis of an aminimide peptide isostere.
Bioorg.Med.Chem., 4:1545-1558, 1996

PubMed Abstract: The essential role of HIV-1 protease (HIV-1 PR) in the viral life cycle makes it an attractive target for the development of substrate-based inhibitors that may find efficacy as anti-AIDS drugs. However, resistance has arisen to potent peptidomimetic drugs necessitating the further development of novel chemical backbones for diversity based chemistry focused on probing the active site for inhibitor interactions and binding modes that evade protease resistance. AQ148 is a potent inhibitor of HIV-1 PR and represents a new class of transition state analogues incorporating an aminimide peptide isostere. A 3-D crystallographic structure of AQ148, a tetrapeptide isostere, has been determined in complex with its target HIV-1 PR to a resolution of 2.5 A and used to evaluate the specific structural determinants of AQ148 potency and to correlate structure-activity relationships within the class of related compounds. AQ148 is a competitive inhibitor of HIV-1 PR with a Ki value of 137 nM. Twenty-nine derivatives have been synthesized and chemical modifications have been made at the P1, P2, P1', and P2' sites. The atomic resolution structure of AQ148 bound to HIV-1 PR reveals both an inhibitor binding mode that closely resembles that of other peptidomimetic inhibitors and specific protein/inhibitor interactions that correlate with structure-activity relationships. The structure provides the basis for the design, synthesis and evaluation of the next generation of hydroxyethyl aminimide inhibitors. The aminimide peptide isostere is a scaffold with favorable biological properties well suited to both the combinatorial methods of peptidomimesis and the rational design of potent and specific substrate-based analogues.

PubMed: 8894111
DOI: 10.1016/0968-0896(96)00147-2

実験手法

X-RAY DIFFRACTION (2.5 Å)