Anti-HIV-1 activity of the neurokinin-1 receptor antagonist aprepitant and synergistic interactions with other antiretrovirals.
OBJECTIVE
Neurokinin-1 receptor (NK1R) antagonists interfere with binding of neuropeptide substance P to NK1R and exhibit novel anti-HIV-1 activities. Since NK1R antagonists effectively penetrate the blood-brain barrier to reduce the inflammatory response within the brain, we wished to evaluate their potential as anti-HIV-1 candidates for targeting HIV-1 infections of the central nervous system.


METHODS
A series of small molecule agents were evaluated for anti-NK1R and anti-HIV-1 activity using peripheral blood mononuclear cells (PBMCs). The most promising of these, aprepitant (Emend, Merck and Co. Inc.), was investigated for potential synergies with other antiretroviral drugs.


METHODS
Anti-NK1R activity was tested by measuring intracellular calcium increase triggered by substance P. Anti-HIV-1 activity was evaluated by measuring p24 antigen in culture supernatants of PBMC following exposure to HIV. The concentration of drug which produced 50% reduction in intracellular calcium levels or viral production in 7-day PBMC cultures was determined. The combined effect of aprepitant with each of the major classes of anti-HIV-1 drugs was evaluated in synergy studies.


RESULTS
Aprepitant had the highest anti-HIV-1 activity of the NK1R antagonists examined and was equally active against all major HIV-1 subtypes. Aprepitant acted synergistically with protease inhibitors (ritonavir and saquinavir), but not with nucleoside reverse transcriptase, non-nucleoside reverse transcriptase, or viral entry inhibitors.


CONCLUSIONS
The ability of aprepitant to penetrate the blood-brain barrier, its safety record as an FDA-approved drug for reducing nausea and vomiting in chemotherapy, and synergistic activity with other anti-HIV-1 drugs make it a promising candidate for treatment of HIV infection.
Manak
Mark M
MM
SeraCare Life Sciences Inc., Gaithersburg, Maryland 20877, USA. mmanak@seracare.com
Moshkoff
Dmitry A
DA
Nguyen
Lequan T
LT
Meshki
John
J
Tebas
Pablo
P
Tuluc
Florin
F
Douglas
Steven D
SD
D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D000077608:Aprepitant; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002493:Central Nervous System Diseases / Q000188:drug therapy* / Q000503:physiopathology / Q000821:virology; D004347:Drug Interactions; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009025:Morpholines / Q000493:pharmacokinetics*; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D015398:Signal Transduction; D013373:Substance P / Q000493:pharmacokinetics
D019380:Anti-HIV Agents; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D000077608:Aprepitant; D013373:Substance P