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

@article{citeulike:1382228, abstract = {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 Ki values of approximately 50 and approximately 20 microM, 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 Ki. Protease inhibition by Glu-Asp-Leu is dependent on a protonated form of a group with a pKa of 3.8; unlike other inhibitors of HIV-1 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 (Ki approximately 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-1 replication.}, address = {Laboratory of Chemical Physics, National Institute of Diabetes, Digestive and Kidney Diseases, The National Institutes of Health, Bethesda, Maryland 20892, USA. jmlouis@helix.nih.gov}, author = {Louis, J. M. and Dyda, F. and Nashed, N. T. and Kimmel, A. R. and Davies, D. R.}, citeulike-article-id = {1382228}, citeulike-linkout-0 = {http://dx.doi.org/10.1021/bi972059x}, citeulike-linkout-1 = {http://pubs.acs.org/doi/abs/10.1021/bi972059x}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/9485357}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=9485357}, comment = {the reference for 1a30}, day = {24}, doi = {10.1021/bi972059x}, issn = {0006-2960}, journal = {Biochemistry}, keywords = {clanokinsa, hiv, pr, protein}, month = {February}, number = {8}, pages = {2105--2110}, posted-at = {2007-06-12 22:53:05}, priority = {1}, title = {Hydrophilic peptides derived from the transframe region of Gag-Pol inhibit the HIV-1 protease.}, url = {http://dx.doi.org/10.1021/bi972059x}, volume = {37}, year = {1998} }

TY - JOUR ID - citeulike:1382228 L3 - citeulike-article-id:1382228 N2 - 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 Ki values of approximately 50 and approximately 20 microM, 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 Ki. Protease inhibition by Glu-Asp-Leu is dependent on a protonated form of a group with a pKa of 3.8; unlike other inhibitors of HIV-1 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 (Ki approximately 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-1 replication. IS - 8 JF - Biochemistry SN - 0006-2960 AD - Laboratory of Chemical Physics, National Institute of Diabetes, Digestive and Kidney Diseases, The National Institutes of Health, Bethesda, Maryland 20892, USA. jmlouis@helix.nih.gov EP - 2110 TI - Hydrophilic peptides derived from the transframe region of Gag-Pol inhibit the HIV-1 protease. VL - 37 SP - 2105 KW - clanokinsa KW - hiv KW - pr KW - protein N1 - the reference for 1a30 AU - Louis, JM AU - Dyda, F AU - Nashed, NT AU - Kimmel, AR AU - Davies, DR PY - 1998/02/24/ UR - http://dx.doi.org/10.1021/bi972059x ER -