Development of antiviral drugs for the treatment of hepatitis C at an accelerating pace

Abstract

Anno 2015, the race for developing the ideal therapy, or what is now called "cure," for hepatitis C virus infection has continued unabatedly. The targets (NS3/4A protease, NS5A protein, and NS5B polymerase) have remained the same, and the number of compounds [direct-acting antivirals (DAAs)] interacting with these targets has continued to increase. Whereas pan-genotypic activity has remained a mandatory requirement, the problem of virus drug resistance has become less crucial. The need for combining DAAs acting at different sites has remained compelling, with the drugs used for combinations emanating from the same pharmaceutical company, that is, Gilead (sofosbuvir and ledipasvir) (Gilead Sciences, Foster City, CA, USA) (AbbVie, North Chicago, IL, USA), AbbVie (ABT/r, ombitasvir, and dasabuvir), and BMS (Bristol-Myers Squibb), (New York City, NY, USA) (asunaprevir and daclatasvir) among the leading contenders. At stake is the definitive cure of HCV infection [as reflected by a sustained viral response (SVR) after 12 weeks of treatment]. This SVR is expected to reduce cirrhosis and hepatocellular carcinoma, two complications inherently linked to HCV infection. Unlike hepatitis B virus and human immunodeficiency virus, HCV infection can be definitely and permanently cured by antiviral therapy because HCV has no long-term reservoir in the body. Peginterferon combined with ribavirin and even the first-wave protease inhibitors telaprevir and boceprevir now belong to the milestones that had an important, although historical, role in the final conquest of hepatitis C.

Electrostatic recognition in substrate binding to serine proteases

“…In humans, more than 560 different genes code for proteases constitute nearly 3% of all approximately 19 000 human genes; therefore, proteases have been investigated as drug targets extensively . Many protease inhibitors are already very successful drugs, eg, to control blood coagulation, to treat hypertension and diabetes, to fight cancer, and to combat viral diseases like HIV and Hepatitis C . However, protease promiscuity and overlapping specificity profiles are major problems that have to be overcome in most protease inhibitor drug design efforts …”

Current therapy for chronic hepatitis C: The role of direct-acting antivirals

“…Before 2011, interferon and ribavirin were the standard of care therapies, whereas they offered rather low clinical effectiveness and caused serious side effects (see reviews elsewhere ( 2009)). The advent of DAAs opened an era to potentially cure HCV in most patients (De Clercq, 2015;De Clercq, 2012;De Clercq, 2014). Between January 2011 and November 2016, there were ten therapies approved by the FDA (Table 1), as well as two approved drugs (asunaprevir þ daclatasvir, vaniprevir þ ribavirin þ PegIFNa) in Japan.…”

“…During the past three years, advancements of HCV drug discovery have been made to produce a large amount of new inhibitors with better potency and safety profiles. In our previous reviews, we described experimental compounds against HCV infections (De Clercq, 2015;De Clercq, 2012;De Clercq, 2014;De Clercq and Li, 2016). In this section, we update the recent progress of anti-HCV agents targeting NS3/4A (Fig.…”

“…Over the past two decades, tremendous attempts have been made to discover antiviral drugs that effectively treat hepatitis C virus (HCV) infection (De Clercq, 2015;De Clercq, 2012;De Clercq, 2014;Welzel et al, 2014;De Clercq and Li, 2016). The first generation of FDA-approved HCV drugs includes: interferon alfacon-1 (approval year: 1997, discontinued in 2013 due to severe adverse events), ribavirin (1998), pegylated interferon alfa-2b (2001), and pegylated interferon alfa-2a (2002).…”

Antivirales (a excepción del VIH y la hepatitis)

“…Lo mismo sucede para los inhibidores no nucleosídicos de las ADN polimerasas, que engloban moléculas de estructuras muy diversas y que se han descrito esencialmente en el caso de la transcriptasa inversa del VIH-1 [1,3] . Los inhibidores de las ARN polimerasas dependientes de ARN son en comparación menos numerosos que los inhibidores de las ADN polimerasas, pero recientemente han tenido un éxito espectacular en el tratamiento de la hepatitis C; también incluyen inhibidores nucleosídicos y no nucleosídicos [6] . Asimismo, hay inhibidores eficaces que se dirigen contra otras proteínas virales que participan directa o indirectamente en la replicación de los genomas virales, como la helicasa que separa las cadenas complementarias del ADN antes de su replicación, la ribonucleótido reductasa que cataliza la producción de desoxirribonucleótidos disfosfato y trifosfato, la integrasa del VIH que permite la integración de la ADN proviral en los cromosomas celulares o la proteína NS5A del VHC, cuyo papel funcional aún no se conoce con detalle [2,3,7] .…”