Alternative approaches to antiviral treatments: focusing on glycosylation as a target for antiviral therapy

Abstract

Development of effective and safe medication for the treatment of viral infections remains a major challenge for the pharmaceutical industry in the 21st Century. There are numerous problems with the existing antiviral treatments both in terms of their safety and, in some cases, their cost, and they cannot be used generally but only in special circumstances. However, the threat of viral diseases ranging from AIDS and hepatitis C to influenza is increasing each year and there is considerable interest in safer and more generally applicable alternative treatments. It has been recognized for some time that some viruses have glycosylation features that are essential to their infectivity, but a means of providing a therapeutic route that is based on this has not been easy to exploit. In recent years, a number of possible approaches have been investigated and some of these are now considered to be realistic forms of therapy. Generally, approaches based on inhibition of the host machinery to glycosylate viral proteins or the ability of compounds to mimic the surface glycosylation of the virus seem to offer the best potential approaches. In this mini-review article, we look at recent advances in both of these areas and their potential to provide a new arsenal of antiviral therapeutics for AIDS, hepatitis C and influenza. Some of these are now entering clinical trials and others are at an advanced stage of preclinical development, but all of them represent good candidates for a therapy that could be more resilient to the problems of viral mutation and diversity.

Addicted to sugar: roles of glycans in the orderMononegavirales

“…The glucose-mimetic N -9-methoxynonyl (DNJ), for example, inhibits a part of the glycosylation pathway, thus preventing viral GPs from folding properly ( Francois and Balzarini 2012 ; Dalziel et al 2014 ). DNJ has been shown to be effective in combating HIV, hepatitis B and C viruses and has been suggested as a possible therapeutic against the flaviviruses dengue virus and West Nile virus ( Merry and Astrautsova 2010 ). Carbohydrate mimetics are suggested to be good drug candidates because they generally have a low toxicity, are water soluble, can be easily modified by adding different functional groups at multiple locations and have the potential to be used as scaffolds for more complex drugs ( Merry and Astrautsova 2010 ).…”

“…DNJ has been shown to be effective in combating HIV, hepatitis B and C viruses and has been suggested as a possible therapeutic against the flaviviruses dengue virus and West Nile virus ( Merry and Astrautsova 2010 ). Carbohydrate mimetics are suggested to be good drug candidates because they generally have a low toxicity, are water soluble, can be easily modified by adding different functional groups at multiple locations and have the potential to be used as scaffolds for more complex drugs ( Merry and Astrautsova 2010 ). However, carbohydrates generally have been thought to make poor drug candidates due to their high polarity, preventing passive transport through the intestinal lining (and thus problematic for oral dosing regimens).…”

“…These virally encoded, cell-executed GPs have the added benefit of being more likely recognized as “self” proteins by the host immune system, thus helping “hide” the virus from host defenses ( Scanlan et al 2007 ; Helle et al 2011 ; Biering et al 2012 ). Viral GPs then contribute to multiple viral functions, including viral entry and immune evasion ( Merry and Astrautsova 2010 ). This has been well characterized in viruses such as HIV, where glycosylation protects the virus from antibody neutralization ( Ogert et al 2001 ; Wei et al 2003 ; Scanlan et al 2007 ; Li et al 2008 ), and for influenza virus, where glycosylation modulates virulence and immune system targeting ( Ohuchi et al 1997 ; Wagner et al 2000 ; Reading et al 2009 ; Tate, Brooks et al 2011 ; Tate, Job et al 2011 ; Tsuchiya, Sugawara, Hongo, Matsuzaki, Muraki et al 2002 ; Tsuchiya, Sugawara, Hongo, Matsuzaki, Muraki et al 2002 ; Vigerust and Shepherd 2007 ; Vigerust et al 2007 ).…”

Bitter-sweet symphony: glycan–lectin interactions in virus biology

“…Considering the various structural and nonstructural roles of glycans, it is clear that glycome modulation can also have effects beyond the alteration of glycan-lectin binding events. For instance, interfering with host cell glycosylation processes using specific inhibitors may inhibit assembly of infectious virions (Leavitt et al, 1977;Katz et al, 1980;Pizer et al, 1980;Herrler & Compans, 1983;Montefiori et al, 1988;Pal et al, 1989;Mehta et al, 1998;Dwek et al, 2002;Wu et al, 2002;Durantel et al, 2007;Lazar et al, 2007;Scanlan et al, 2007;Durantel, 2009;Merry & Astrautsova, 2010). Moreover, glycome modulation may significantly alter the capacity of the virus to evade recognition by virus-specific antibodies and B-and T-cell receptors via glycan shielding (Botarelli et al, 1991;Back et al, 1994;Willey et al, 1996;Reitter et al, 1998;Bolmstedt et al, 2001;Kang et al, 2005;Aguilar et al, 2006;Wang et al, 2009;Francica et al, 2010;Kobayashi & Suzuki, 2012).…”

Recombinant rabbit single‐chain antibodies bind to the catalytic and C‐terminal domains of HIV‐1 integrase protein and strongly inhibit HIV‐1 replication

“…However, the emergence of drug-resistant virus isolates is causing an increasingly detrimental impact on disease outcome [5],[6]. As a result, there is a pressing need to identify and develop new therapies that can be effective against virus isolates resistant to HAART [7],[8]. …”