Single oral administration of the novel CXCR4 antagonist, KRH-3955, induces an efficient and long-lasting increase of white blood cell count in normal macaques, and prevents CD4 depletion in SHIV-infected macaques: a preliminary study

Abstract

We evaluated the long-term effects of the single oral administration of a new CXCR4 antagonist, KRH-3955, on elevation of white blood cell (WBC), neutrophil and lymphocyte counts in normal cynomolgus monkeys. In the monkeys treated with 0, 2, 20, 200 mg/kg of the compound, WBC, neutrophil and lymphocyte counts increased dramatically at 2 days after treatment. This effect was dose-dependent, and these cell counts remained elevated 15 days after drug treatment. Since neutrophils are the most abundant WBCs in circulation and bone marrow neutrophil exhaustion impairs the response to bacterial infections, it is intriguing to exploit this pharmacological increase of neutrophils as a tool to address its influence on viral infections in vivo. The SHIV infection studies using the SHIV-KS661c/cynomolgus monkey model showed that a single oral administration of KRH-3955 (100 mg/kg) approximately 24 h before virus exposure did not prevent infection, although it did prevent CD4 cell depletion in 3/3 monkeys. Furthermore, single oral administration of the drug 2 weeks before viral exposure rescued CD4 cells in 1/3 monkeys. This prevention of CD4 cell depletion was observed in both blood and lymphoid tissues. These results show that natural course of the SHIV infection is modulated by artificial increase of neutrophils and lymphocytes caused by KRH-3955 in the cynomolgus monkey model.

Two distinct CXCR4 antagonists mobilize progenitor cells in mice by different mechanisms

“…22 Our results show that a single administration of KRH3955 (30 mg/kg) induced mobilization of leukocytes and HPCs in mice, with largely elevated numbers in the circulation after 2 h. The number of circulating cells returned to baseline by 24 hours (Figure 4A-B). Peak mobilization coincided with a significant decrease in CXCL12 levels in the BM, but no changes were detected in the plasma levels of CXCL12 (Figure 4C-D).…”

“…Previous studies in primates demonstrated that KRH3955 induces an increase in circulating leukocytes, but we are the first to demonstrate that KRH3955 mobilizes HPCs into the blood. 22 Interestingly, KRH3955 does not mobilize MPCs in VEGF-A pretreated mice, suggesting that reversal of the CXCL12 chemokine gradient is critical for mobilization of MPCs.…”

“…21 As with AMD3100, preliminary studies investigating the anti-HIV activity of KRH3955 showed that a single dose of this drug elevated leukocyte counts in peripheral blood. 22 Here, we have made use of a specific CXCL12 neutraligand, chalcone 4-phosphate, 23,24 to address the question of whether an elevation of CXCL12 in the plasma is required for mobilization of HPCs and MPCs by these distinct CXCR4 antagonists.…”

Increased HIV-1 sensitivity to neutralizing antibodies by mutations in the Env V3-coding region for resistance to CXCR4 antagonists

“…This compound is orally bioavailable and has higher anti-HIV-1 activity in vitro compared with AMD3100 (Murakami et al, 2009). A single oral administration of KRH-3955 prevented CD4 depletion in X4-tropic simian-human immunodeficiency virus infection (Nakasone et al, 2013). Several mutant viruses less sensitive to CXCR4 antagonists (referred to as CXCR4 antagonistresistant viruses) have been reported (Kanbara et al, 2001;Schols et al, 1998;de Vreese et al, 1996).…”

Double Oral Administration of Emtricitabine/Tenofovir Prior to Virus Exposure Protects against Highly Pathogenic Simian/Human Immunodeficiency Virus Infection in Macaques

“…Group 1 was treated with a double dose of FTC/TDF (20/30 mg/kg) 24 h and a few minutes prior to viral exposure; group 2 was given a single dose of FTC/TDF (20/30 mg/kg) 2 weeks before viral exposure; and group 3 (naä ƒve control group) was not treated with any drug. The study was divided into 2 research reports including the current manuscript and the previously published study (27); group 3 was the same in both papers. The drug was formulated in 3 ml of water and was administered intragastrically via a nasal feeding tube under anesthesia.…”