As an effort to develop novel antiviral compounds, we are developing KNI-272, a transition-state mimetic tripeptide HIV protease inhibitor containing allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenyl- butyric acid]. KNI-272 was first administered to patients with advanced HIV-1 infection at the Medicine Branch in March 1994. We have now found that certain mutations occurring in the protease-encoding region can confer on HIV-1 resistance to KNI 272 in vitro. We have more recently identified several Apns-containing protease inhibitors which are active against both wild-type HIV-1 and HIV-1 variants resistant to KNI-272. The accumulating data suggest that the development of HIV-1 variants with reduced susceptibility to reverse transcriptase (RT) inhibitors is related to clinical deterioration in patients receiving combination therapy with multiple RT inhibitors (e.g., AZT/ddC and AZT/ddI). In this regard, we have identified a set of novel mutations [Ala-62 Val(A62V), V75I, F77L, F116Y, and Q151M] in the polymerase domain of RT of HIV-1, which confers on the virus a reduced sensitivity to multiple antiretroviral dideoxynucleosides (ddNs). We have recently defined virological and enzymatic properties of such mutations. In another area of our research efforts to optimize the antiviral activity of nucleoside RT inhibitors, we have demonstrated differential anti-HIV-1 activity of ddNs in phytohemagglutinin-activated peripheral blood mononuclear cells (PHA-PBM) and resting PBM. We have also found that hydroxyurea (HU) can potentiate antiviral activity of ddNs, particularly that of ddI, through inhibition of deoxyribonucleotide reductase. These data suggest that modification of certain cellular enzymes may enhance the antiviral activity of anti-HIV-1 drugs, which may open a new avenue in designing combination chemotherapy of AIDS.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC006738-05
Application #
2464463
Study Section
Special Emphasis Panel (M)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
1996
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Takamatsu, Yuki; Das, Debananda; Kohgo, Satoru et al. (2018) The High Genetic Barrier of EFdA/MK-8591 Stems from Strong Interactions with the Active Site of Drug-Resistant HIV-1 Reverse Transcriptase. Cell Chem Biol 25:1268-1278.e3
Ghosh, Arun K; Gemma, Sandra; Baldridge, Abigail et al. (2008) Flexible cyclic ethers/polyethers as novel P2-ligands for HIV-1 protease inhibitors: design, synthesis, biological evaluation, and protein-ligand X-ray studies. J Med Chem 51:6021-33
Ghosh, Arun K; Chapsal, Bruno D; Weber, Irene T et al. (2008) Design of HIV protease inhibitors targeting protein backbone: an effective strategy for combating drug resistance. Acc Chem Res 41:78-86
Maeda, Kenji; Das, Debananda; Yin, Philip D et al. (2008) Involvement of the second extracellular loop and transmembrane residues of CCR5 in inhibitor binding and HIV-1 fusion: insights into the mechanism of allosteric inhibition. J Mol Biol 381:956-74
Nakata, Hirotomo; Steinberg, Seth M; Koh, Yasuhiro et al. (2008) Potent synergistic anti-human immunodeficiency virus (HIV) effects using combinations of the CCR5 inhibitor aplaviroc with other anti-HIV drugs. Antimicrob Agents Chemother 52:2111-9
Mitsuya, Hiroaki; Maeda, Kenji; Das, Debananda et al. (2008) Development of protease inhibitors and the fight with drug-resistant HIV-1 variants. Adv Pharmacol 56:169-97
Koh, Yasuhiro; Matsumi, Shintaro; Das, Debananda et al. (2007) Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule inhibitors of protease dimerization. J Biol Chem 282:28709-20
Harada, Shigeyoshi; Hazra, Rohan; Tamiya, Sadahiro et al. (2007) Emergence of human immunodeficiency virus type 1 variants containing the Q151M complex in children receiving long-term antiretroviral chemotherapy. Antiviral Res 75:159-66
Nakata, Hirotomo; Amano, Masayuki; Koh, Yasuhiro et al. (2007) Activity against human immunodeficiency virus type 1, intracellular metabolism, and effects on human DNA polymerases of 4'-ethynyl-2-fluoro-2'-deoxyadenosine. Antimicrob Agents Chemother 51:2701-8
Amano, Masayuki; Koh, Yasuhiro; Das, Debananda et al. (2007) A novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI), GRL-98065, is potent against multiple-PI-resistant human immunodeficiency virus in vitro. Antimicrob Agents Chemother 51:2143-55

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