Frontiers in Clinical Drug Research: Anti-Infectives

Inflammation is a physiological process caused when an agent (chemical, biological or physical) transcends the primary defense barrier of an organism, setting a series of biological reactions to restore the integrity of such organism, thus playing a central role in the fight against those pathogens. Uncontrolled amplification of these events may lead to undesirable pathological manifestations such as cancer, diabetes, and cardiovascular, neurological, and chronic inflammatory diseases. Monoclonal antibodies (mAbs) were first described in 1975, and since then, they have proven to be relevant therapeutic agents in a myriad of diseases. The US Food and Drug Administration (FDA) has already approved more than 90 mAbs for the treatment of several diseases, from which approximately 26% were specifically approved for the treatment of inflammatory diseases, for instance, rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, and palmoplantar pustulosis. This chapter provides an overview of the inflammation process and main biochemical mechanisms, together with a vision on the current state of the art of the mAbs-based biopharmaceuticals market and their application as powerful therapeutic agents for inflammatory diseases.

Anti-infective agents have been one of the greatest accomplishments of modern medicine, which has led to a decrease in the number of deaths caused by various infectious diseases. The anti-infective agents are a broad family consisting of antimicrobials, antifungals, antimalarials, antiprotozoal, antituberculosis, and antiviral agents. Viral infections have caused millions of casualties worldwide, leading to the need for the development of effective antiviral agents. Although the replication mechanism differs significantly between the viruses, all viruses undergo steps like attachment, entry, genome replication, gene expression, and assembly for the release of the virions into the body of the host. Treatment with antiviral agents is essential for blocking the replication of the virus, and the currently available antiviral therapies are directed according to the disease. Furthermore, the treatment with antiviral agents aims to eradicate the viral pathogen from the host and prevent the clinical manifestation. Infectious diseases, such as human immunodeficiency virus (HIV), hepatitis B, and hepatitis C virus (HBV and HCV), and influenza, are of significant global concern. On the contrary, the outbreak of newer strains of influenza virus and Zika virus, Ebola virus, strains of coronavirus (CoV) like severe acute respiratory syndrome (SARS – CoV), Middle East respiratory syndrome (MERS – CoV) and novel Coronavirus (2019-nCoV) are life-threatening viral infections that exhibit major challenges to the humanity. As of date, multiple effective virostatics that target specific viral replication steps are approved for the treatment of viral infections. However, the use of such agents is restricted given the rapid emergence of antiviral resistance, which remains a major concern of current antiviral therapy. In this chapter, we summarize recent antiviral agents that show promising clinical benefits in various phases of clinical trials and also consider them as potential therapeutic agents in the future. Besides, we highlight and analyze the development of novel inhibitors targeting various stages of the viral life cycle that act by distinct mechanisms against current and emerging viral infections. Many antiviral drugs currently available are based on the concept of traditional chemotherapy. Nevertheless, new developments and advances in molecular biology have opened up possibilities to alternate treatment approaches. Clinical trials to evaluate gene silencing mediated by small interfering RNA (siRNA) and antisense RNAs expression against infection with a respiratory syncytial virus (RSV) have recently been initiated. Moreover, in–vitro studies of antisense RNA or siRNA technology have shown promising results in various virus strains. Despite the recent advancements, the development of targeted delivery of antiviral RNA molecules remains a major challenge since DNA viruses and retroviruses can incorporate their genomes into human genomes. To emphasize, antiviral drugs against particular target proteins have been effective in the treatment of prevalent infectious diseases such as HIV and HCV. Thereupon, broad-spectrum antiviral drugs instead of antivirals against specific virus infections need to be designed. With the rapid development of in-silico tools and gene modification strategies, antiviral drugs with better therapeutic index and safety profile will be developed against infectious diseases in the future. In fact, the effective design of newer antiviral drugs will reduce the possibility of emerging antiviral resistance.

Innate and adaptive immune responses, which are intimately related to the evolution of many infectious diseases, are influenced by the biologically active form of vitamin D. From a mechanical perspective, there are several rationales to assume that vitamin D positively modifies host responses to SARS-CoV-2, either in the early infection or subsequent hyper-inflammatory stages of COVID-19. It has been long known that vitamin D metabolites induce antiviral effects through indirect and direct mechanisms via antimicrobial peptides, immune modulation, the interaction between major viral and cellular particles, initiation of apoptosis and autophagy, and diversity of hereditary and epigenetic aspects. The remarkable overlap between the deficiency of vitamin D and risk factors for severe COVID-19, including obesity, aging, and Black or Asian ethnicity, has motivated researchers to assume that supplementation of vitamin D can be promising as a preventive or treatment agent for COVID-19. Since the outset of the pandemic, researchers have integrated literature searches and crosssectional statistical studies to appraise the vitamin D level impact of COVID-19, whereby nearly 30 observational studies have confirmed that the incidence, severity, and mortality of COVID-19 are inversely related to the serum 25OHD concentrations. Also, some recently announced clinical trials indicated that vitamin D supplementation has a positive effect on the severity of COVID-19; however, other studies, including clinical trials, have not supported that, especially if we take into account what was revealed in a recent clinical trial, i.e., airway diseases are related to the irregular metabolism of vitamin D increasing the potential of developing vitamin D deficiency due to pulmonary inflammation. Therefore, more dedicated studies are required without critical limitations to ascertain the actual effect of vitamin D in preventing and treating COVID-19, and if its effectiveness is proven, the effective dose must be determined.

Anti-infectives, by definition, refers to the drugs that can act against infection either by inhibiting the spread of infectious agents or killing them outright. These include a plethora of compounds that encompass antibiotics, anti-fungals, antihelmintics, anti-malarials, anti-leishmanials, anti-protozoals, anti-tuberculosis, and antivirals properties. This chapter is dedicated to specifically focus on articles related to the anti-leishmanial therapeutics which entails drug development, techniques to improvise drug delivery, and identification of new cost-effective better therapeutics which would have immense potential to overcome all the limitations of the present-day therapies. Leishmaniasis is a dreaded parasitic disease caused by the protozoan parasites of the genus Leishmania. It can be categorized into three types: cutaneous, mucocutaneous, and visceral, amongst which visceral leishmaniasis (VL) is a neglected tropical disease that results in significant morbidity and mortality worldwide. Approximately 500,000 new cases per year of visceral leishmaniasis (VL) are supposed to occur globally, of which 90% of the new cases are found to affect just five countries, including India. Therapeutic measures those in vogue, again pose a number of serious limitations related to toxicity, lengthy regime, drug side effects, drug resistance, and cost, making overall treatment a complex issue. Again, VL poses unique problems in different settings which is a major threat for the choice of treatment. Furthermore, fundamental differences in the behavior of the causative parasites and the response of the host to the pathogen in different settings may also vary which can complicate the choice of treatment. The healthcare provision for VL patients in India is not up to the mark as it is a poorly standardized system of private care, which is associated with relatively high costs, thus making treatment difficult for the poor population. This is especially a ‘disease of the poor' mostly affecting the lower socio-economic population who is malnourished and cannot strictly abide by regular monitoring or follow-ups during treatment owing to poverty reasons. Drug resistance has become a growing limitation because the partially recovered patients has the possibility of developing parasites resistant to treatment due to insufficient drug dosage, which in turn gets transmitted to new patients causing primary drug resistance. To alleviate all these problems of current therapies encountered so far, it is a necessity of paramount importance to explore and develop new drugs that can enrich the known small armamentarium of anti-leishmanials. Discovering new chemotherapeutics that are cheap, effective, less toxic and capable to overcome drug resistance will help to better combat the disease. Available treatment options are quite limited, and planning to switch to combination therapy is also equally important, as it can scale up treatment efficacy. Overall, this chapter aims to highlight the challenges of the current antileishmanial therapies, coupled with the unraveling of the new therapeutic modalities and their mechanisms of action which potentiates them as better anti-leishmanial agents, thereby overcoming the problems of present-day therapeutics. Furthermore, it will also shed light on the importance of various immunomodulators and investigational drugs which might come up as effective, remedial therapeutics against leishmaniasis, in the future trials.

Nematode parasites cause several neglected tropical diseases in humans such as lymphatic filariasis, onchocerciasis (river blindness), and soil-transmitted helminthiasis. Approximately 30% of the human world population is infected with at least one parasite and this prevalence could be even higher in rural areas and lowincome countries. Although nematode infections are rarely lethal, they are associated with morbidity and severe consequences, particularly in children.

There are several concerns about the management and treatment of these diseases. Currently, the repertoire of nematocidal agents is limited, and these drugs are not 100% effective against all nematode parasitosis. In addition, the extensive use of these few drugs in massive administration campaigns in humans would probably lead to the development of resistance very soon. Further worsening the situation, the interest of the pharmacological industry in developing novel anthelmintics is low since these infections are mostly endemic in poor countries that do not constitute a profitable market. Under this alarming scenario, there is an urgent need to develop new and broad-spectrum antiparasitic drugs.

Traditional preclinical drug discovery is a long, expensive, and complex process. Thus, innovative strategies and alternative models, such as the free-living nematode Caenorhabditis elegans, are required to reduce costs and accelerate times. Its genetic amenability and the feasibility of performing high-throughput screening assays, convert this nematode into an excellent platform for nematocidal drug screening.

This chapter summarizes the current situation on antiparasitic drug discovery and discusses the use of C. elegans at the initial steps of drug development to accelerate the appearance of new drugs.

Zika virus is a mosquito-borne disease initially limited to sporadic cases in Africa and Asia. With the recent emergence of the Zika virus in Brazil in 2015, the virus rapidly spread throughout America. Even though most of the Zika virus infections have a mild influenza-like illness, severe manifestations were also observed, including Guillain-Barre syndrome in adults and microcephaly in babies born to infected mothers. Due to the severity of this disease, structural virologists quickly studied its different features. But, even with the elucidation of the viral genome, an effective treatment or suitable vaccine is not available for this disease so far. The viral vectors, pathogenesis, genetic diversity, and co-infection with other diseases remain unanswered. The production of an effective vaccine is hence a global health concern. This chapter discusses the emergence of the Zika virus and its detailed genome structure and replication cycle. The molecular pathogenesis and Zika viral therapeutics with detailed descriptions about the host and viral targets, investigational drugs, and vaccine candidates are explained here.

Agro-industrial waste production represents an environmental problem, and its processing results in the obtainment of by-products that are rich sources of bioactive compounds. Apis mellifera are social insects that create the ideal conditions for the transmission of pathogens. American foulbrood (AFB) is the main pathology that affects bee brood; the causative agent is the Gram-positive bacteria Paenibacillus larvae. During the last years, there have been significant losses of hives by the use of synthetic antimicrobials for the control of AFB. The presence of antibiotics in honey and other products of the hive have generated concern in consumers regarding the risks of toxicity, negatively influencing the time of marketing and export. On the other hand, there is the possibility of the appearance of resistance by pathogenic microorganisms caused by incomplete treatments or an overdose of the antibiotic used. More than 70 plant extracts have been evaluated in vitro and in vivo against P. larvae; for this reason, the revaluation of biological waste material from agroindustry is being studied through pharmacodynamic and pharmacognosy analysis both in P. larvae and in the different stages of development of A. mellifera.

Therefore, this chapter proposes to investigate: (1) the effect of the application of fertilizer treatment on the hop cultivar in the composition and amount of secondary metabolites, (2) the bioactivity of extracts of hop leaves against P. larvae, and in vitro toxicity in larvae and adult bees, and the effect on genes of the immune system of bees.