In this report period, we carried on our long-standing research line, development of anti-HIV drugs, however, we particularly focused our effort to develop antiretroviral agents which resist the emergence of drug-resistant HIV-1 variants, in response to the rapidly growing problem, drug failure in patients with HIV-1 infection. We also made efforts to enhance/improve antiviral efficacy in patients by physiologically altering cellular metabolisms. Over the past four years, we designed and synthesized ~300 potential HIV protease inhibitors in collaborations with intra- and extramural investigators and identified JE-2147, a novel allophenylnorstatine (apns)-containing dipeptide HIV protease inhibitor (PI) potent against a wide spectrum of HIV-1, HIV-2, SIV, and clinical HIV-1 strains, and in particular, against multi-PI-resistant HIV-1 strains with IC50 values ranging from 13-41 nM in vitro. Our structural analysis revealed that the presence of a flexible P2i moiety is important for the potency of JE-2147 toward wild type and mutant viruses. These data suggest that the use of flexible components may open a new avenue for designing PIs which resist the emergence of PI-resistant HIV-1 (Proc. Natl. Acad. Sci. USA, 96: 8675-80, 1999). It is of note that JE 2147 is currently undergoing preclinical and clinical development in the US. Most recently, we have identified another novel protease inhibitor, UIC-003, in collaboration with scientists in University of Chicago and NCI-FCRDC. This novel compound is extremely potent against HIV-1 with IC50 values of less than nanomolar concentrations (~0.5 nM). UIC-003 is also potent against multi-PI-resistant clinical strains at nanomolar concentrations (ranging from 1-6 nM). An HIV-1 population, which was propagated in vitro in the presence of increasing concentrations of UIC 003 and became less susceptible to the compound, still had IC50 values of 0.01 microM, which appear to be relatively easily maintained in vivo. Such HIV-1 mutants had a unique mutation at codon 28 of the protease-encoded gene, indicating that this novel compound binds to a unique site (or subsites) of the target protease. In 1993, we identified a set of novel mutations [Ala-62

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC006738-09
Application #
6435190
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2000
Total Cost
Indirect Cost
Name
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
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
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

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