Peptide HIV-1 Integrase Inhibitors from HIV-1 Gene Products

Suzuki, Shintaro; Urano, Emiko; Hashimoto, Chie; Tsutsumi, Hiroshi; Nakahara, Toru; Tanaka, Tomohiro; Nakanishi, Yuta; Maddali, Kasthuraiah; Han, Yan; Hamatake, Makiko; Miyauchi, Katsumi; Pommier, ﻿Yves; Beutler, John A.; Sugiura, Wataru; Fuji, Hideyoshi; Hoshino, Tyuji; Itotani, Kyoko; Nomura, Wataru; Narumi, Tetsuo; Yamamoto, Naoki; Komano, Jun; Tamamura, Hirokazu

doi:10.1021/jm1003528

Cited by 38 publications

(34 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results suggest that the O-allyltyrosine analogues function via an alternative mechanism to previously reported peptide based inhibitors and the LEDGF/p75 allosteric inhibitors. For example the previously reported Vpr-and Env-derived peptides inhibit both 3'-processing and ST, 36 similarly both series of cell-permeable stapled Vpr-derived 35 , IN-derived 34 peptides and combinatorial-derived hexapeptides 45 are also inhibitors of both 3'-processing and ST. To date, the only other reported peptide analogue to specifically inhibit ST was a heptapeptide which also displays cationic character. 46 Moreover the previously reported series of small molecule inhibitors of the LEDGF/p75 interaction were equipotent against 3'-processing and ST 26 whilst the most recently reported LEDGF/p75 inhibitor GSK1264 is a potent inhibitor of 3'-processing.…”

Section: Resultsmentioning

confidence: 66%

The discovery of allyltyrosine based tripeptides as selective inhibitors of the HIV-1 integrase strand-transfer reaction

et al. 2016

View full text Add to dashboard Cite

show abstract

Section: Resultsmentioning

confidence: 66%

The discovery of allyltyrosine based tripeptides as selective inhibitors of the HIV-1 integrase strand-transfer reaction

et al. 2016

View full text Add to dashboard Cite

show abstract

“…The parent compound 5 showed significant anti-HIV activity at concentrations above 1.25 µM, as reported previously (Figure 4). 4 Compound 15 showed a significant inhibitory effect against HIV-1 replication, and is thus comparable to compound 5 . Compounds 11 , 14 and 16 also displayed weak antiviral effects at concentrations of 2.5 and 5.0 µM and compounds 12 , 13 and 17 failed to show any significant anti-HIV activity.…”

Section: Resultsmentioning

confidence: 92%

“…The virus, as well as the host cells, must encode mechanism(s) to prevent auto-integration since the regulation of IN activity is critical for the virus to infect cells 3. By screening a library of overlapping peptides derived from HIV-1 SF2 gene products we have found three Vpr-derived peptides, 1 , 2 and 3 , which possess significant IN inhibitory activity, indicating that IN inhibitors exist in the viral pre-integration complex (PIC) 4. The above inhibitory peptides, 1 , 2 and 3 , are consecutive overlapping peptides (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Peptidic HIV integrase inhibitors derived from HIV gene products: Structure–activity relationship studies

Suzuki

Hashimoto

Urano

et al. 2010

Bioorganic & Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

Structure-activity relationship studies were conducted on HIV integrase (IN) inhibitory peptides which were found by the screening of an overlapping peptide library derived from HIV-1 gene products. Since these peptides located in the second helix of Vpr are considered to have an alpha-helical conformation, Glu-Lys pairs were introduced into the i and i+4 positions to increase the helicity of the lead compound possessing an octa-arginyl group. Ala-scan was also performed on the lead compound for the identification of the amino acid residues responsible for the inhibitory activity. The results indicated the importance of an alpha-helical structure for the expression of inhibitory activity, and presented a binding model of integrase and the lead compound.

show abstract

“…MT-4 Luc cells (human T lymphocytic cell line expressing luciferase constitutively) were infected with HIV-1 (HXB2 strain) and incubated at 37°C in the presence of the test compounds. In this T cell system, the luciferase activity is reduced by HIV-1 infection, due to the cell death upon HIV-1 replication (31). When added to HIV-1-infected MT-4 Luc cells, one of the candidates (172A6) recovered the luciferase expression in a dose-dependent manner (Fig.…”

Section: Screening Of a Chemical Library For Gag-gag Interaction Inhimentioning

confidence: 94%

Novel Postentry Inhibitor of Human Immunodeficiency Virus Type 1 Replication Screened by Yeast Membrane-Associated Two-Hybrid System

Urano

Kuramochi

Ichikawa

et al. 2011

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Human immunodeficiency virus (HIV)Gag protein targets to the plasma membrane and assembles into viral particles. In the next round of infection, the mature Gag capsids disassemble during viral entry. Thus, Gag plays a central role in the HIV life cycle. Using a yeast membrane-associated two-hybrid assay based on the SOS-RAS signaling system, we developed a system to measure the Gag-Gag interaction and isolated 6 candidates for Gag assembly inhibitors from a chemical library composed of 20,000 small molecules. When tested in the human MT-4 cell line and primary peripheral blood mononuclear cells, one of the candidates, 2-(benzothiazol-2-ylmethylthio)-4-methylpyrimidine (BMMP), displayed an inhibitory effect on HIV replication, although a considerably high dose was required. Unexpectedly, neither particle production nor maturation was inhibited by BMMP. Confocal microscopy confirmed that BMMP did not block Gag plasma membrane targeting. Single-round infection assays with envelope-pseudotyped and luciferase-expressing viruses revealed that BMMP inhibited HIV replication postentry but not simian immunodeficiency virus (SIV) or murine leukemia virus infection. Studies with HIV/SIV Gag chimeras indicated that the Gag capsid (CA) domain was responsible for the BMMP-mediated HIV postentry block. In vitro studies indicated that BMMP accelerated disassembly of HIV cores and, conversely, inhibited assembly of purified CA protein in a dosedependent manner. Collectively, our data suggest that BMMP primarily targets the HIV CA domain and disrupts viral infection postentry, possibly through inducing premature disassembly of HIV cores. We suggest that BMMP is a potential lead compound to develop antiretroviral drugs bearing novel mechanisms of action.Over 2 decades, research has developed antiretroviral therapy (ART) with a combination of antiretroviral drugs for human immunodeficiency virus type 1 (HIV-1) infection (10). ART has dramatically improved the survival of HIV-1-infected individuals. Current ART involves a combination of inhibitors of HIV-specific enzymes, such as protease (PR), reverse transcriptase (RT), and integrase (IN). In some cases, inhibitors of HIV-1 entry are also used. However, the emergence of HIV-1 variants resistant to antiretroviral drugs during ART stresses the need for novel HIV-1 inhibitors against distinct targets.Multiple screening approaches have been employed for HIV-1 drug discovery (37) and have successfully discovered HIV-1 inhibitors that are currently available: nucleoside analogue RT inhibitors were discovered by HIV replication assays (23) and PR inhibitors were produced by structure-based drug design (25). In general, cell-free assays allow discovery of compounds with a relatively low 50% effective dose (ED 50 ) in vitro. However, many such compounds often fail to inhibit HIV-1 replication in in vivo assays, because they may not penetrate the cell membrane or may easily be catalyzed in metabolic environments. Also, possible toxic effects of the compounds must be tested in a subsequent c...

show abstract

Peptide HIV-1 Integrase Inhibitors from HIV-1 Gene Products

Cited by 38 publications

References 25 publications

The discovery of allyltyrosine based tripeptides as selective inhibitors of the HIV-1 integrase strand-transfer reaction

The discovery of allyltyrosine based tripeptides as selective inhibitors of the HIV-1 integrase strand-transfer reaction

Peptidic HIV integrase inhibitors derived from HIV gene products: Structure–activity relationship studies

Novel Postentry Inhibitor of Human Immunodeficiency Virus Type 1 Replication Screened by Yeast Membrane-Associated Two-Hybrid System

Contact Info

Product

Resources

About