Viral genome targeting for antiviral drug discovery and vaccine development

Abstract

First discovered by Dmitri Ivanovsky in 1892, viruses hold a cardinal role in infection biology. Viruses are the smallest entities that need a living system for their growth and proliferation. Viruses can infect all kinds of organisms, including animals, plants, and even bacteria. They have played a vital role in shaping the evolutionary process. While not all viruses cause disease, many of them can induce mild to severe illnesses in plants, animals, and humans. From ancient Egyptian sculpture showing evidence of poliomyelitis to modern SARS-CoV-2 associated pathology, viral diseases are continually being reported worldwide. Interestingly, the emergence of novel viral strains as a result of the interplay between viral evolution and the host is a matter of great concern. Viral factors like genetic mutations, reassortments, and rearrangements, natural selection, cross-species migration, etc. contribute to the advent of new viral variants. At the same time, other components like environmental and climatic changes, human physiological determinants, social activities including population density, global trade, travel, urbanization, socioeconomic conditions, poor hygiene, and improper use of drugs massively add up to the cause. To cope with the scenario, continuous research and development activities are needed to find potential antiviral medicines and vaccines simultaneously. In the past years, notable progress in the front of the antiviral drug has been made to control viruses like; Human immunodeficiency virus I (HIV-I), Herpes simplex virus (HSV), Varicella Zoster virus, Hepatitis B virus (HBV), Hepatitis C virus (HCV), Influenza virus, etc. But the emergence of new viral strains, drug resistance, and availability of fewer drug-targets brings additional challenges in this domain. Unlike any other living creature, the viral genome is unique in its genetic composition, having either RNA or DNA as the genetic material. In this aspect, nucleic acid secondary structures hold the affirmative scope to act as ligand binding sites. Specifically, the guanine-rich sequences folding into G-quadruplex (GQ) structures have immensely gained attention in the field of drug discovery. Stretches of guanine residues interspersed by any other nucleotide align themselves to form a framework of planar tetrad with the help of non-canonical Hoogsteen bonds, which further stack up to form the quadruplex motif. Presence of cellular ions such as potassium, sodium, etc. aid in assembling the structure by nullifying the negative charges of oxygen atoms in the guanine residues. Many scientific evidences show the presence and relevance of these GQ structures in various organisms, including humans, plants, bacteria, yeast, and even viruses. With the probability of more than 300,000 putative GQs in the human genome, these motifs are extensively reported to be associated with the telomere stability and maintenance, promoter activity of different genes like Bcl2, c-Myc, KRAS, etc., rearrangements in immunoglobulin genes, chromosome stability, epigenetic modulations, etc. in humans. In vivo visualization of the GQ structures in human cells and the studies suggesting the association of helicases in the unknotting of these secondary structures further, strengthen the functional importance of GQs in the cellular milieu. Moreover, the strategical designing of GQ-specific ligands like Quarfloxin has set the motion for targeting the potential GQ structures in the human genome for treating diseases like cancer. Similarly, microorganisms, like viruses, bear functional GQ structures that have been exploited for drug targeting. Precisely, the viral genomes, including HSV, Human papillomavirus, Zika virus, Pseudorabies virus, etc. contain a sizeable number of potential GQ forming sequences. Some of these have functional importance in the viral promoters modulating the viral gene regulation specifically, the transcription and replication process in viruses such as HBV, HSV, HIV, and Pseudorabies viruses. Thus, the availability of a plethora of knowledge on viral genetics and accessibility to the testing tools led us to hypothesize that these signature sequences in the viral genome are the target for developing antiviral compounds.