The Epidemiology and pathogenesis of HIV Influenza
Every year, influenza epidemics cause numerous deaths and millions of hospitalizations, but the most frightening effects are seen when new strains of the virus emerge from different species (e.g. the swine-origin influenza A/H1N1 virus), causing worldwide outbreaks of infection.
Several antiviral compounds may have been re-developed against any influenza virus that may want to interfere with the specific events in the supposed replication cycle.
Currently, there are a number of approved antiviral agents for use in the treatment of viral infections. However, many instances exist in which the use of a second antiviral agent would be beneficial because it would allow the option of either an alternative or a combination therapeutic approach.
Accordingly, virus-encoded proteases have emerged as new targets for antiviral intervention. Current molecular studies and research have indicated a supposedly viral proteases which has always played a critical role in the life cycle of many viruses by affecting the cleavage of high-molecular-weight viral polyprotein precursors to yield functional products or by catalyzing the processing of the structural proteins necessary for assembly and morphogenesis of virus particles.
This review summarizes some of the important general features of virus-encoded proteases and highlights new advances and/or specific challenges that are associated with the research and development of viral protease inhibitors. Specifically, the viral protease encoded by the HIV is discussed.
Human Influenza Reveals The Dynamic Nature Of viral Genome Evolution
Although drugs capable of inhibiting virus replication were described in the scientific literature as early as the 1950s (Jitet al., 2013), only recently has the development of new antiviral agents with activity against virus-specific functions made rapid progress.
To date, 20 different antiviral chemotherapeutic agents have been approved for use in the treatment of individuals infected with a variety of different viruses (Jitet al., 2013; Postma et al., 2006). Although the majority of these agents are used primarily for the treatment of herpesvirus and human immunodeficiency virus (HIV) infections, respiratory syncytial virus and influenza A virus infections can also be treated (Holmes et al., 2005).
Since the discovery that viruses contain nucleic acid genomes, which undergo replication as part of the virus life cycle, the early antiviral drug design efforts paralleled those in the research and development of antiproliferative agents for the treatment of cancer.
Accordingly, the majority of the approved antiviral agents are nucleoside analogs which act by inhibiting viral DNA synthesis (herpesvirus) or viral reverse transcription (HIV) (Holmes et al., 2005).
Despite these advances, the use of most of these antiviral chemotherapeutic agents was characterized by limited clinical efficacy, adverse side effects, and suboptimal pharmacokinetics (Dolan et al., 2013).
Of equal concern was the emergence of drug-resistant viral strains in individuals who required chronic therapy for effective clinical management of their infection, since the development of drug-resistant variants can severely affect and limit subsequent treatment options.
Due to these concerns, it was clear that the development of new antiviral agents with activity against new virus-specific targets was warranted. Recent technological advances have facilitated greater understanding of the molecular biology and biochemistry of the viral enzymes which are involved in the viral life cycle (Thomas et al., 2013).
In particular, viral enzymes that are essential for the production of infectious virus represent potential therapeutic targets. Research and development of inhibitors directed to these antiviral targets has been aided by other advances such as high-throughput screening of compound libraries and rationally based drug approaches based on X-ray crystallography (Udell et al., 2013).
During the last decade, preclinical research efforts have centered on virus-encoded proteases as potential targets for antiviral intervention (Poole et al., 2006 Abramson et al., 2012).
These studies have indicated that viral proteases are an absolute requirement in the life cycle of many viruses, either by affecting the cleavage of high-molecular-weight precursor viral proteins to yield functional products or by catalyzing the processing of the structural proteins necessary for assembly and morphogenesis of viral particles.
Furthermore, the clinical efficacy of antiviral agents designed to target proteases has been demonstrated in HIV-infected individuals whose therapeutic regimens contain one of four recently approved HIV specific protease inhibitors (Cates and Rowe, 2013).
This review will summarize some of the important general features of virus-encoded proteases, specifically highlighting new advances and the specific challenges associated with the design, discovery, and subsequent development of viral protease inhibitors (Beck et al., 2012).
Although viral proteases play critical roles in the life cycle of many different virus families, this review focuses on the proteases encoded by the herpesvirus, retrovirus, hepatitis C virus (HCV), and human rhinovirus (HRV) families. Detailed information describing the structure and function of viral proteases has been extensively reviewed by other authors (Jefferson et al., 2010; Beck et al., 2012) and is not covered here.