Influenza virus infection of neonates poses a major health concern, often resulting in severe disease and hospitalization. At present, vaccines for this at-risk population are lacking. Thus, development of an effective vaccine is an urgent need. Here we have used an innovative nonhuman primate neonate challenge model to test the efficacy of a novel TLR 7/8 agonist (R848) conjugated influenza virus vaccine. The use of the intact virus represents a step forward in conjugate vaccine design as it provides multiple antigenic targets allowing for elicitation of a broad immune response. Our results show that this vaccine induces high level virus-specific antibody and cell mediated responses in neonates that result in increased virus clearance and reduced lung pathology following challenge compared to the non-adjuvanted virus vaccine. Surprisingly, the addition of a second TLR agonist (flagellin) did not enhance vaccine protection, suggesting combinations of TLR that provide increased efficacy must be determined empirically. These data support further exploration of this new conjugate influenza vaccine approach as a platform for use in the at-risk neonate population.

Withania somnifera (Ashwagandha) is an important Rasayana herb and widely considered as Indian ginseng in Ayurveda. In traditional system of Indian medicine, it is used as tonic to rejuvenate the body and increase longevity. In Ayurvedic preparations, various parts of the plant have been used to treat variety of ailments that affect the human health. However, dried roots of the plant are widely used for the treatment of nervous and sexual disorders. The major active chemical constituents of this plant are withanolides, which is responsible for its wide range of biological activities. Since the beginning of the 20 th century, a significant amount of research has been done and efforts are ongoing to further explore other bioactive constituents, and many pharmacological studies have been carried out to describe their disease preventing mechanisms. In this chapter, we have reviewed the chemistry and pharmacological basis of W. somnifera in various human ailments.

The natural products colchicine and combretastatin A-4 (CA4) are potent inhibitors of tubulin assembly, and they have inspired the design and synthesis of a large number of small-molecule, potential anticancer agents. The indole-based molecular scaffold is prominent among these SAR modifications, leading to a rapidly increasing number of agents. The water-soluble phosphate prodrug 33 (OXi8007) of a 2-aryl-3-aroylindole-based phenol 8 (OXi8006) was prepared by chemical synthesis and found to be strongly cytotoxic against selected human cancer cell lines (GI50 = 36 nM against DU-145 cells, for example). The free phenol, 8 (OXi8006), was a strong inhibitor (IC50 = 1.1 µM) of tubulin assembly. The corresponding phosphate prodrug 33 (OXi8007) also demonstrated pronounced interference with tumor vasculature in a preliminary in vivo study utilizing a SCID mouse model bearing an orthotopic PC-3 (prostate) tumor as imaged by color Doppler ultrasound. The combination of these results provides evidence that the indole-based phosphate prodrug 33 (OXi8007) functions as a vascular disrupting agent (VDA) that may prove useful for the treatment of cancer.

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The phenomenon of antibiotic resistance has created a need for the development of novel antibiotic classes with nonclassical cellular targets. Unfortunately, target-based drug discovery against proteins considered essential for in vitro bacterial viability has yielded few new therapeutic classes of antibiotics. Targeting the large proportion of genes considered nonessential that have yet to be explored by high-throughput screening, for example, RecA, can complement these efforts. Recent evidence suggests that RecA-controlled processes are responsible for tolerance to antibiotic chemotherapy and are involved in pathways that ultimately lead to full-fledged antibiotic resistance. Therefore inhibitors of RecA may serve as therapeutic adjuvants in combination chemotherapy of bacterial infectious diseases. Toward the goal of validating RecA as a novel target in the chemotherapy of bacterial infections, the authors have screened 35,780 small molecules against RecA. In total, 80 small molecules were identified as primary hits and could be clustered in 6 distinct chemotype clades. The most potent class of hits was further examined, and 1 member compound was found to inhibit RecA-mediated strand exchange and prevent ciprofloxacin-induced SOS expression in Escherichia coli. This compound represents the first small molecule demonstrating an ability to inhibit the bacterial SOS response in live bacterial cell cultures.