Hydrophilic peptides derived from the transframe region of Gag-Pol inhibit the HIV-1 protease

被引:80
作者
Louis, JM
Dyda, F
Nashed, NT
Kimmel, AR
Davies, DR
机构
[1] NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA
[2] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA
[3] NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA
[4] NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA
关键词
D O I
10.1021/bi972059x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The HIV-1 transframe region (TFR) is between the structural and functional domains of the Gag-Pol polyprotein, flanked by the nucleocapsid and the protease domains at its N and C termini, respectively, Transframe octapeptide (TFP) Phe-Leu-Arg-Glu-Asp-Leu-Ala-Phe, the N terminus of TFR, and its analogues are competitive inhibitors of the action of the mature HIV-1 protease. The smallest, most potent analogues are tripeptides: Glu-Asp-Leu and Glu-Asp-Phe with K-i values of similar to 50 and similar to 20 mu M, respectively, Substitution of the acidic amino acids in the TFP by neutral amino acids and D or retro-D configurations of Glu-Asp-Leu results in an >40-fold increase in K-i, Protease inhibition by Glu-Asp-Leu is dependent on a protonated form of a group with a pK(a), of 3.8; unlike other inhibitors of HIV-I protease which are highly hydrophobic, Glu-Asp-Leu is extremely soluble in water, and its binding affinity decreases with increasing NaCl concentration. However, Glu-Asp-Leu is a poor inhibitor (K-1 similar to 7.5 mM) of the mammalian;aspartic acid protease pepsin. X-ray crystallographic studies at pH 4.2 show that the interactions of Glu at P2 and Leu at P1 of Glu-Asp-Leu with residues of the active site of HIV-1 protease are similar to those of other product-enzyme complexes, It was not feasible to understand the interaction of intact TFP with HIV-1 protease under conditions of crystal growth due to its hydrolysis giving rise to two products. The sequence-specific, selective inhibition of the HIV-1 protease by the viral TFP suggests a role for TFP in regulating protease function during HIV-I replication.
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页码:2105 / 2110
页数:6
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