Substance P and its role in viral infection
Wenya Xu, Tongsong Wang, Hongwei Zhou
Review Article : Int J Clin Exp Med 2018;11(12):12946-12955
Substance P (SP) is an 11-amino acid neuropeptide of the tachykinin family that preferentially activates the neurokinin-1 receptor (NK1R). Early studies identified a role for SP and the NK1R in the digestive system, respiratory system, urogenital system, skin, nervous system, immune system, and tumors. More recently, SP and the NK1R have gained attention for their role in multiple viral infections, such as human immunodeficiency virus (HIV), HSV (herpes simplex keratitis), encephalomyocarditis virus (EMCV), respiratory syncytical virus (RSV), measles virus (MV), Epstein-Barr virus (EBV), enterovirus 71 (EV71) and so on. However, to date no human clinical assays using NK-1 receptor antagonists against viral infections have been developed, expect HIV. The use of aprepitant as antiHIV therapy has been tested in human clinical trials, although this NK-1 receptor antagonist showed no significant anti-viral activity. NK-1 receptor antagonists merit further investigation as potential therapeutic antiviral agents. In this review, we update the involvement of the SP/NK-1 receptor system in viral infections, with the aim of providing insights for future anti-viral chemotherapy studies.
Neurokinin-1 receptor antagonists: A new revolution in antiretroviral treatment?
Udhayvir Singh Grewal
Indian J Sex Transm Dis AIDS. 2016 Jul-Dec; 37(2): 208–209.
In the goal of complete eradication of human immunodeficiency virus (HIV), antiretroviral drug resistance seems to be a serious obstacle. It has been predicted that despite the approval of newer anti-retroviral drugs, emergence of resistance against them is almost inevitable. This necessitates the development of anti-HIV drugs with newer targets and mechanisms of action along with activity against drug-resistant viruses.
Neurokinin-1 receptor (NK1R), a receptor for the neuropeptide substance P (SP), is a member of family 1 (rhodopsin-like) of G protein-coupled receptors. These receptors are found widely distributed in both the central and the peripheral nervous systems. NK1R antagonists are drugs that interfere with binding of neuropeptide SP to NK1R. Aprepitant, an NK1R antagonist, is currently used clinically for the prevention of nausea and vomiting associated with cancer chemotherapy or following surgical procedures. Surprisingly, it also possesses novel anti-HIV properties.
SP and NK1R are known to be central mediators in the interaction between the nervous and the immune systems. SP has been shown to not only increase HIV replication but also enhance the expression of membrane-bound CD163 in monocytes. Macrophages derived from monocytes with high levels of membrane-bound CD163 have increased susceptibility to HIV infection. SP also inhibits natural killer (NK) cell cytotoxicity through NK1R.
Aprepitant has been found to be active against HIV drug-resistant isolates and enhance the anti-HIV activity of various anti-retroviral drugs. According to the results obtained by a phase 1B trial of aprepitant in HIV-1 infected adults, the drug was reported to decrease plasma levels of SP and soluble CD163. In addition, aprepitant treatment was also shown to be associated with decreased expression of programmed death 1 receptor which suppresses T-cell activation; Along with a decrease in plasma levels of several pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor alpha, which when raised, are associated with poorer prognosis in chronic HIV infection. It also inhibits the negative immunomodulatory effects of SP on NK cells.
In yet another study done by Wang et al., aprepitant was found to inhibit infection of macrophages with zidovudine (AZT)-resistant and reverse transcriptase inhibitor-resistant viruses. It was also found to significantly increase the anti-HIV activity of antiretroviral drugs such as AZT, efavirenz, and indinavir. Both aprepitant and the non-peptide NK1R antagonist CP-96,345 inhibit CCR5 receptor expression on macrophages, which is required for the entry of HIV into macrophages. Manak et al. showed the operation of additional antiviral mechanisms not involving CCR5 in monocytes. NK1R antagonists can also help in preventing inflammatory and neurocognitive events associated with HIV infection, which remains a challenge today in most patients even after successful treatment. It is a safe drug with the only significant side effect being an increase in the incidence of infection.
Therefore, aprepitant is a promising candidate that is set to revolutionize anti-retroviral treatment by not only curbing the emergence of drug resistance but also adding to the net therapeutic effect of combination antiretroviral therapy by virtue of its synergistic effects. Extensive research on this group of drugs as therapeutic and immunomodulatory agents against HIV is currently underway.
Anti-HIV-1 Activity of the Neurokinin-1 Receptor Antagonist Aprepitant and Synergistic Interactions with other Antiretrovirals
Mark M. MANAK,1 Dmitry A. MOSHKOFF,1 Lequan T. NGUYEN,1 John MESHKI,2 Pablo TEBAS,3 Florin TULUC,2,4 and Steven D. DOUGLAS2,4
AIDS. Author manuscript; available in PMC 2012 Jun 19.
Objectives.- Neurokinin-1 receptor (NK1R) antagonists interfere with binding of neuropeptide substance P (SP) 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.
Design.- A series of small molecule agents were evaluated for anti-NK1R and anti-HIV-1 activity using peripheral blood mononuclear cells (PBMC). 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.
Conclusion.- 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.
Substance P receptor antagonism: a potential novel treatment option for viral-myocarditis
Prema Robinson 1, George E Taffet 1, Nikita Engineer 1, Mitra Khumbatta 1, Bahrom Firozgary 1, Corey Reynolds 2, Thuy Pham 1, Tushar Bulsara 1, Gohar Firozgary 1
Biomed Res Int. 2015;2015:645153. doi: 10.1155/2015/645153. Epub 2015 Mar 2.
Viral-myocarditis is an important cause of heart failure for which no specific treatment is available. We previously showed the neuropeptide substance P (SP) is associated with the pathogenesis of murine myocarditis caused by encephalomyocarditis virus (EMCV). The current studies determined if pharmacological inhibition of SP-signaling via its high affinity receptor, NK1R and downstream G-protein, Ras homolog gene family, member-A (RhoA), will be beneficial in viral-myocarditis. Aprepitant (1.2 mg/kg), a SP-receptor antagonist, or fasudil (10 mg/kg), a RhoA inhibitor, or saline control was administered daily to mice orally for 3 days, prior to, or 5 days following, intraperitoneal infection with and without 50 PFU of EMCV, following which disease assessment studies, including echocardiogram and cardiac Doppler were performed in day 14 after infection. Pretreatment and posttreatment with aprepitant significantly reduced mortality, heart and cardiomyocyte size, and cardiac viral RNA levels (P < 0.05 all, ANOVA). Only aprepitant pretreatment improved heart functions; it significantly decreased end systolic diameter, improved fractional shortening, and increased peak aortic flow velocity (P < 0.05 all, ANOVA). Pre- or posttreatment with fasudil did not significantly impact disease manifestations. These findings indicate that SP contributes to cardiac-remodeling and dysfunction following ECMV infection via its high affinity receptor, but not through the Rho-A pathway. These studies suggest that SP-receptor antagonism may be a novel therapeutic-option for patients with viral-myocarditis.