Design, Synthesis, and Antiviral Evaluation of Chimeric Inhibitors of HIV Reverse Transcriptase

被引：7

作者：

Iyidogan, Pinar ^{[1
]}

Sullivan, Todd J. ^{[1
]}

Chordia, Mahendra D. ^{[2
]}

Frey, Kathleen M. ^{[1
]}

Anderson, Karen S. ^{[1
]}

机构：

[1] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA

[2] Chemin Pharma, New Haven, CT 06511 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2013年 / 4卷 / 12期

关键词：

HIV; reverse transcriptase; nucleoside H-phosphonate; NNRTI; synthesis; POTENTIAL MULTIFUNCTIONAL INHIBITORS; BIFUNCTIONAL INHIBITION; DEOXYCYTIDINE KINASE; MOLECULAR-MECHANISM; HETERODIMERS; NUCLEOSIDE; ABACAVIR; PRODRUG; SITE;

D O I：

10.1021/ml4002979

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In a continuing study of potent bifunctional anti-HIV agents, we rationally designed a novel chimeric inhibitor utilizing thymidine (THY) and a TMC derivative (a diarylpyrimidine NNRTI) linked via a polymethylene linker (ALK). The nucleoside, 5'-hydrogen-phosphonate (H-phosphonate), and S'-triphosphate forms of this chimeric inhibitor (THY-ALK-TMC) were synthesized and the antiviral activity profiles were evaluated at the enzyme and cellular level. The nucleoside triphosphate (11) and the H-phosphonate (10) derivatives inhibited RT polymerization with an IC50 value of 6.0 and 4.3 nM, respectively. Additionally, chimeric nucleoside (9) and H-phosphonate (10) derivatives reduced HIV replication in a cell-based assay with low nanomolar antiviral potencies.

引用

页码：1183 / 1188

页数：6

共 41 条

[1] MAMMALIAN DEOXYRIBONUCLEOSIDE KINASES
ARNER, ESJ
ERIKSSON, S
[J]. PHARMACOLOGY & THERAPEUTICS, 1995, 67 (02) : 155 - 186
[2] Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy
Bailey, Christopher M.
Sullivan, Todd J.
Iyidogan, Pinar
Tirado-Rives, Julian
Chung, Raymond
Ruiz-Caro, Juliana
Mohamed, Ebrahim
Jorgensen, William
Hunter, Roger
Anderson, Karen S.
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (10) : 3959 - 3968
[3] Defining a molecular mechanism of synergy between nucleoside and nonnucleoside AIDS drugs
Basavapathruni, A
Bailey, CM
Anderson, KS
[J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (08) : 6221 - 6224
[4] Modulation of human immunodeficiency virus type 1 synergistic inhibition by reverse transcriptase mutations
Basavapathruni, Aravind
Vingerhoets, Johan
de Bethune, Marie-Pierre
Chung, Raymond
Bailey, Christopher M.
Kim, Jiae
Anderson, Karen S.
[J]. BIOCHEMISTRY, 2006, 45 (23) : 7334 - 7340
[5] CHABRIER P, 1957, CR HEBD ACAD SCI, V245, P174
[6] High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: Strategic flexibility explains potency against resistance mutations
Das, Kalyan
Bauman, Joseph D.
Clark, Arthur D., Jr.
Frenkel, Yulia V.
Lewi, Paul J.
Shatkin, Aaron J.
Hughes, Stephen H.
Arnold, Eddy
[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (05) : 1466 - 1471
[7] COMPARISON OF THE SUBSTRATE SPECIFICITIES OF HUMAN THYMIDINE KINASE-1 AND KINASE-2 AND DEOXYCYTIDINE KINASE TOWARD ANTIVIRAL AND CYTOSTATIC NUCLEOSIDE ANALOGS
ERIKSSON, S
KIERDASZUK, B
MUNCHPETERSEN, B
OBERG, B
JOHANSSON, NG
[J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1991, 176 (02) : 586 - 592
[8] Synthesis and anti-HIV activity of [D4U]-[Trovirdine analogue] and [D4T]-[Trovirdine analogue] heterodimers as inhibitors of HIV-1 reverse transcriptase
Gavriliu, D
Fossey, C
Ciurea, A
Delbederi, Z
Sugeac, E
Ladurée, D
Schmidt, S
Laumond, G
Aubertin, AM
[J]. NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS, 2002, 21 (8-9) : 505 - 533
[9] Drug design - Discovering high-affinity ligands for proteins
Hajduk, PJ
Meadows, RP
Fesik, SW
[J]. SCIENCE, 1997, 278 (5337) : 497 - &
[10] Structure of a covalently trapped catalytic complex of HIV-I reverse transcriptase: Implications for drug resistance
Huang, HF
Chopra, R
Verdine, GL
Harrison, SC
[J]. SCIENCE, 1998, 282 (5394) : 1669 - 1675

← 1 2 3 4 5 →