Puromycin-sensitive aminopeptidase: an antiviral prodrug activating enzyme.
Puromycin-sensitive aminopeptidase: an antiviral prodrug activating enzyme.
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DOI：
10.1016/j.antiviral.2009.12.003
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发表时间：
2010-03
影响因子：
7.6
通讯作者：
Amidona, Gordon L.
中科院分区：
文献类型：
--
作者：
Tehler, Ulrika;Nelson, Cara H.;Peterson, Larryn W.;Provoda, Chester J.;Hilfinger, John M.;Lee, Kyung-Dall;McKenna, Charles E.;Amidona, Gordon L.
Cidofovir (HPMPC) is a broad-spectrum antiviral agent, currently used to treat AIDS-related human cytomegalovirus retinitis. Cidofovir has recognized therapeutic potential for orthopox virus infections, although its use is hampered by its inherent low oral bioavailability. Val-Ser-cyclic HPMPC (Val-Ser-cHPMPC) is a promising peptide prodrug which has previously been shown by us to improve the permeability and bioavailability of the parent compound in rodent models ( vol 5 598-609). Puromycin-sensitive aminopeptidase was partially purified from Caco-2 cell homogenates and identified as a prodrug activating enzyme for Val-Ser-cHPMPC. The prodrug activation process initially involves an enzymatic step where the l-Valine residue is removed by puromycin-sensitive aminopeptidase, a step that is bestatin-sensitive. Subsequent chemical hydrolysis results in the generation of cHPMPC. A recombinant puromycin-sensitive aminopeptidase was generated and its substrate specificity investigated. The kcat for Val-pNA was significantly lower than that for Ala-pNA, suggesting that some amino acids are preferred over others. Furthermore, the three-fold higher kcat for Val-Ser-cHPMPC as compared to Val-pNA suggests that the leaving group may play an important role in determining hydrolytic activity. In addition to its ability to hydrolyze a variety of substrates, these observations strongly suggest that puromycin-sensitive aminopeptidase is an important enzyme for activating Val-Ser-cHPMPC in vivo. Taken together, our data suggest that puromycin-sensitive aminopeptidase makes an attractive target for future prodrug design.
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影响因子：
4.9
作者：
Eriksson, Ulrika;Peterson, Larryn W.;McKenna, Charles E.
通讯作者：
McKenna, Charles E.
DOI：
10.1039/p29800000373
发表时间：
1980-01-01
期刊：
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 2
影响因子：
--
作者：
LAZARUS, RA;BENKOVIC, PA;BENKOVIC, SJ
通讯作者：
BENKOVIC, SJ
影响因子：
2.3
作者：
McKenna, CE;Kashemirov, BA;Hilfinger, JM
通讯作者：
Hilfinger, JM
影响因子：
3.9
作者：
JOHNSON, GD;HERSH, LB
通讯作者：
HERSH, LB
影响因子：
15
作者：
LAZARUS, RA;BENKOVIC, SJ
通讯作者：
BENKOVIC, SJ