The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
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Murakami T, Kumakura S, Yamazaki T, Tanaka R, Hamatake M, Okuma K, Huang W, Toma J, Komano J, Yanaka M, Tanaka Y, Yamamoto N
The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100.
Antimicrob Agents Chemother. 2009 Jul;53(7):2940-8. doi: 10.1128/AAC.01727-08. Epub 2009 May 18.
- PubMed ID
- 19451305 [ View in PubMed]
- Abstract
The previously reported CXCR4 antagonist KRH-1636 was a potent and selective inhibitor of CXCR4-using (X4) human immunodeficiency virus type 1 (HIV-1) but could not be further developed as an anti-HIV-1 agent because of its poor oral bioavailability. Newly developed KRH-3955 is a KRH-1636 derivative that is bioavailable when administered orally with much more potent anti-HIV-1 activity than AMD3100 and KRH-1636. The compound very potently inhibits the replication of X4 HIV-1, including clinical isolates in activated peripheral blood mononuclear cells from different donors. It is also active against recombinant X4 HIV-1 containing resistance mutations in reverse transcriptase and protease and envelope with enfuvirtide resistance mutations. KRH-3955 inhibits both SDF-1alpha binding to CXCR4 and Ca(2+) signaling through the receptor. KRH-3955 inhibits the binding of anti-CXCR4 monoclonal antibodies that recognize the first, second, or third extracellular loop of CXCR4. The compound shows an oral bioavailability of 25.6% in rats, and its oral administration blocks X4 HIV-1 replication in the human peripheral blood lymphocyte-severe combined immunodeficiency mouse system. Thus, KRH-3955 is a new promising agent for HIV-1 infection and AIDS.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Plerixafor C-X-C chemokine receptor type 4 IC 50 (nM) 289.1 N/A N/A Details