Posts Tagged ‘Drugs’

Reasons to be cheeful: Influenza treatment

Friday, April 11th, 2014

Lung immunity against influenza virus As we find out that Tamiflu is no more effective than paracetamol or ibuprofen in treating influenza infection (NHS Choices: Effectiveness of Tamiflu and Relenza questioned) – giving Ben Goldacre the right to say I told you so – maybe there is some reason to be more optimistic about treating influenza.

A new paper in Immunity [subscription] shows that prostaglandin E2 (PGE2) is upregulated during influenza A virus infection, and this inhibits macrophage recruitment to the lungs as well as interferon production and apoptosis in influenza virus-infected macrophages. This results in impaired macrophage antigen presentation and reduced adaptive immunity against influenza virus. The good news is that suppression of PGE2 with prostaglandin inhibitors protects against influenza infection. And we’ve got lots of prostaglandin inhibitors, including ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDs) that work by inhibiting a molecule called cyclooxygenase (COX). The lung innate immune system has a critical role in limiting respiratory viral infections, particularly in the case of the nastier strains of flu such as the 1918 Spanish Influenza virus (and those still to come). So this is potentially very good news.

The catch? Well this paper refers to studies in mice and clinical trials will need to be done in humans to show the same effects. Clinical trials will be easy to do as many COX- and PGE-inhibitors are already approved for human use. All we need to do is avoid Roche doing the trial, or we may never find out the results.

Targeted Prostaglandin E2 Inhibition Enhances Antiviral Immunity through Induction of Type I Interferon and Apoptosis in Macrophages. Immunity, 10 April 2014 doi: http://dx.doi.org/10.1016/j.immuni.2014.02.013
Summary: Aspirin gained tremendous popularity during the 1918 Spanish Influenza virus pandemic, 50 years prior to the demonstration of their inhibitory action on prostaglandins. Here, we show that during influenza A virus (IAV) infection, prostaglandin E2 (PGE2) was upregulated, which led to the inhibition of type I interferon (IFN) production and apoptosis in macrophages, thereby causing an increase in virus replication. This inhibitory role of PGE2 was not limited to innate immunity, because both antigen presentation and T cell mediated immunity were also suppressed. Targeted PGE2 suppression via genetic ablation of microsomal prostaglandin E-synthase 1 (mPGES-1) or by the pharmacological inhibition of PGE2 receptors EP2 and EP4 substantially improved survival against lethal IAV infection whereas PGE2 administration reversed this phenotype. These data demonstrate that the mPGES-1-PGE2 pathway is targeted by IAV to evade host type I IFN-dependent antiviral immunity. We propose that specific inhibition of PGE2 signaling might serve as a treatment for IAV.

[Editorial comment: I can just imaging the authors and journal editors doing the happy dance that this paper came out on sthe same day as the Tamiflu news.]

HIV cure research – advances and prospects

Thursday, March 20th, 2014

HIV reservoirs Thirty years after the identification of HIV, a cure for HIV infection is still to be achieved. Advances of combined antiretroviral therapy (cART) (=HAART) in recent years have transformed HIV infection into a chronic disease when treatment is available. However, in spite of the favorable outcomes provided by the newer therapies, cART is not curative and patients are at risk of developing HIV-associated disorders. Moreover, universal access to antiretroviral treatment is restricted by financial obstacles. This review discusses the most recent strategies that have been developed in the search for an HIV cure and to improve life quality of people living with HIV.

Highlights:

  • Some cases of cure or remission of infection have boosted the search for an HIV cure.
  • cART intensification has not shown significant impact in the reservoirs, but early cART may limit them.
  • Strategies to purge the reservoirs face difficulties linked to the complexity of latency mechanisms and drug non-specificity.
  • Repression of reservoirs or cell manipulation to render them less permissive to HIV may facilitate HIV remission.
  • HIV cure/remission may require boosting immune responses while keeping inflammation in check.

 

HIV cure research: Advances and prospects. (2014) Virology pii: S0042-6822(14)00065-8. doi: 10.1016/j.virol.2014.02.021

Bacteriocins – a viable alternative to antibiotics?

Wednesday, January 30th, 2013

Bacteriocin-N Solutions are urgently required for the growing number of infections caused by antibiotic-resistant bacteria. Bacteriocins, which are antimicrobial peptides produced by certain bacteria, might warrant serious consideration as alternatives to traditional antibiotics. These molecules exhibit significant potency against other bacteria (including antibiotic-resistant strains), are stable and can have narrow or broad activity spectra. Bacteriocins can even be produced in situ in the gut by probiotic bacteria to combat intestinal infections. Although the application of specific bacteriocins might be curtailed by the development of resistance, an understanding of the mechanisms by which such resistance could emerge will enable researchers to develop strategies to minimize this potential problem.

 

Bacteriocins – a viable alternative to antibiotics? (2013) Nat Rev Microbiol. 11(2): 95-105. doi: 10.1038/nrmicro2937

Antifungal Drug Discovery – Something Old and Something New

Monday, September 10th, 2012

Cryptococcus Invasive fungal infections are devastating. Despite state-of-the-art antifungal therapy, the mortality rates for invasive infections with the three most common species of human fungal pathogens are Candida albicans, 20%–40%; Aspergillus fumigatus, 50%–90%; and Cryptococcus neoformans, 20%–70%. Although invasive fungal infections can affect people with intact immune systems, the vast majority of disease occurs in the setting of an immunocompromised host.

The dismal outcomes for invasive fungal infections cannot be completely attributed to a lack of efficacious antifungal drugs. However, because most patients with invasive fungal infections are immunocompromised, the immune system cannot effectively assist in the clearance of the infection, and consequently, the success of treatment is more dependent on the efficacy of the antifungal agent than in the setting of an immunocompetent host. Unfortunately, our repertoire of antifungal agents is limited, particularly in comparison to the number of agents available for bacterial infections. In fact, it took 30 years for the newest class of antifungal drugs, the echinocandins, to progress from bench-to-beside. Furthermore, it is sobering to consider that the gold standard therapy for cryptococcal meningitis, a disease that kills more than 650,000 per year world-wide, is based on medications (amphotericin B and flucytosine) that were discovered nearly 50 years ago.

 

Antifungal Drug Discovery: Something Old and Something New. (2012) PLoS Pathog 8(9): e1002870. doi:10.1371/journal.ppat.1002870

Genital human papillomaviruses – current and prospective therapies

Friday, February 24th, 2012

HPV Infection with human papillomaviruses is very common and associated with benign and malignant epithelial proliferations of skin and internal squamous mucosae. A subset of the mucosal HPVs are oncogenic and associated with 5% of all cancers in men and women. There two licensed prophylactic vaccines, both target HPV 16 and 18, the two most pathogenic, oncogenic types and one, additionally, targets HPV 6 and 11 the cause of genital warts.

The approach of deliberate immunisation with oncogenic HPV E6 and/or E7 proteins and the generation of antigen specific cytotoxic T cells as an immunotherapy for HPV associated cancer and their high grade precancers has been tested with a wide array of potential vaccine delivery systems in Phase I/II trials with varying success. Understanding local viral and tumour immune evasion strategies is a prerequisite for the rational design of therapeutic vaccines for HPV associated infection and disease, progress in this is discussed. There are no anti-viral drugs for the treatment of HPV infection and disease.

Current therapies are not targeted anti-viral therapies but either attempt physical removal of the lesion or induce inflammation and a bystander immune response. There has been recent progress in the identification and characterisation of molecular targets for small molecule antagonists of the HPV proteins E1, E2 and E6 or their interactions with their cellular targets. Lead compounds that could disrupt E1:E2 protein/protein interactions have been discovered as have inhibitors of E6:E6-AP binding interactions. Some of these compounds showed nanomolar affinities and high specificities and demonstrate the feasibility of this approach for HPV infections. These studies are, however at early phase, and it is unlikely that any specific anti-HPV chemotherapeutic will be in the clinic within 10-20 years.

 

Genital human papillomaviruses – current and prospective therapies. J Gen Virol. 8 Feb 2012

Effect of antimalarial drugs on the parasite life cycle

Thursday, February 23rd, 2012

Antimalarial drugs A paper in this week’s PLoS Medicine compares the activity of 50 current and experimental antimalarials against liver, sexual blood, and mosquito stages of selected human and nonhuman parasite species, including Plasmodium falciparum, Plasmodium berghei and Plasmodium yoelii. These results provide a valuable guide to help researchers decide which drugs and compounds show most promise as potential future antimalarial drugs for blocking the transmission of malaria.

 

The Activities of Current Antimalarial Drugs on the Life Cycle Stages of Plasmodium Life Cycle: A Comparative Study with Human and Rodent Parasites. (2012) PLoS Med 9(2): e1001169. doi:10.1371/journal.pmed.1001169
Background: Malaria remains a disease of devastating global impact, killing more than 800,000 people every year—the vast majority being children under the age of 5. While effective therapies are available, if malaria is to be eradicated a broader range of small molecule therapeutics that are able to target the liver and the transmissible sexual stages are required. These new medicines are needed both to meet the challenge of malaria eradication and to circumvent resistance.
Methods and Findings: Little is known about the wider stage-specific activities of current antimalarials that were primarily designed to alleviate symptoms of malaria in the blood stage. To overcome this critical gap, we developed assays to measure activity of antimalarials against all life stages of malaria parasites, using a diverse set of human and nonhuman parasite species, including male gamete production (exflagellation) in Plasmodium falciparum, ookinete development in P. berghei, oocyst development in P. berghei and P. falciparum, and the liver stage of P. yoelii. We then compared 50 current and experimental antimalarials in these assays. We show that endoperoxides such as OZ439, a stable synthetic molecule currently in clinical phase IIa trials, are strong inhibitors of gametocyte maturation/gamete formation and impact sporogony; lumefantrine impairs development in the vector; and NPC-1161B, a new 8-aminoquinoline, inhibits sporogony.
Conclusions: These data enable objective comparisons of the strengths and weaknesses of each chemical class at targeting each stage of the lifecycle. Noting that the activities of many compounds lie within achievable blood concentrations, these results offer an invaluable guide to decisions regarding which drugs to combine in the next-generation of antimalarial drugs. This study might reveal the potential of life-cycle–wide analyses of drugs for other pathogens with complex life cycles.

Antibiotic resistance is ancient

Wednesday, February 8th, 2012

Antibiotics An unfailing observation over the past 70 years is that resistance to all antibiotics emerges eventually after use in the clinic. Where does this resistance come from? Recent work has shown that antibiotic resistance genes are common in metagenomes of ancient sediments. This prevalence of resistance, well before the use of antibiotics, denotes the importance of taking microbial chemical ecology and deep metagenomic profiling into account in the development and use of antibiotics.

 

Antibiotic resistance is ancient: implications for drug discovery. Trends Microbiol. 25 Jan 2012

The Next Opportunity for Anti-Malaria Drugs: The Liver

Monday, September 26th, 2011

Malaria life cycle Humans have suffered from the burden of malarial infections for thousands of years, and the disease has greatly influenced human evolution and history. Malaria remains a devastating disease, and in developing countries within Africa, South America, and Asia, the size of its burden has stifled economic growth and development. Despite successful eradication campaigns in North America and Europe, global cases of the disease show little decline, and current improvements rely on pyrethroid treated bed nets and combination therapeutics containing artemisinin derivatives, both of which are susceptible to emerging resistance. Our ability to counter these vulnerabilities with new agents is hampered by the modest number of fully validated drug targets and our limited understanding of many aspects of parasite biology.

 

The Next Opportunity in Anti-Malaria Drug Discovery: The Liver Stage. (2011) PLoS Pathog 7(9): e1002178. doi:10.1371/journal.ppat.1002178
Malaria afflicts 350–500 million people annually, and this debilitating and deadly infectious disease exacts a heavy toll on susceptible populations around the globe. Efforts to find effective, safe, and low-cost drugs for malaria have sharply increased in recent years. Almost all of these efforts have focused on the cyclic blood stage of the disease, partly because the parasites can be easily maintained in culture through addition of human red blood cells to the growth medium, and partly because blood stage infection causes malaria’s characteristic symptoms. However, the asymptomatic liver stage, which the parasite goes through only once in its life history, presents the best opportunity for developing drugs that both hit new targets and also could be used in highly desirable eradication campaigns. Recent research, especially on the frequency of differentially expressed genes in blood and liver stage parasites, supports the feasibility of discovering stage-specific drugs. Discovering these drugs will require a high-throughput liver stage phenotypic screen comparable to the existing blood stage screens, and the basic tools for such a screen have recently been created.

Is bacterial fatty acid synthesis a valid target for antibacterial drug discovery?

Monday, September 5th, 2011

Fatty acids The emergence of resistance against most current drugs emphasizes the need to develop new approaches to control bacterial pathogens, particularly Staphylococcus aureus. Bacterial fatty acid synthesis is one such target that is being actively pursued by several research groups to develop anti-Staphylococcal agents. Recently, the wisdom of this approach has been challenged based on the ability of a Gram-positive bacterium to incorporate extracellular fatty acids and thus circumvent the inhibition of de novo fatty acid synthesis. The generality of this conclusion has been challenged, and there is enough diversity in the enzymes and regulation of fatty acid synthesis in bacteria to conclude that there is not a single organism that can be considered typical and representative of bacteria as a whole. We are left without a clear resolution to this ongoing debate and await new basic research to define the pathways for fatty acid uptake and that determine the biochemical and genetic mechanisms for the regulation of fatty acid synthesis in Gram-positive bacteria. These crucial experiments will determine whether diversity in the control of this important pathway accounts for the apparently different responses of Gram-positive bacteria to the inhibition of de novo fatty acid synthesis in presence of extracellular fatty acid supplements.

 

Is bacterial fatty acid synthesis a valid target for antibacterial drug discovery? Curr Opin Microbiol. Aug 20 2011