Introduction
Successes and Challenges in Antiviral Drug Development

Zhengqiang Wang1 and Michael J. Sofia2

1 Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA

2 Arbutus Biopharma, Inc., 701 Veterans Circle, Warminster, PA 18974, USA

Introduction

Viral infections have had a profound impact on socioeconomics and life expectancy of human societies throughout human history [1-7]. However, the discovery and development of specific antiviral drugs to treat viral diseases has a relatively short history, largely concomitant with the advent of modern biomedical sciences. Specifically, the FDA approval of idoxuridine (IDU) [8] in 1963, a deoxynucleoside analog first synthesized by Prusoff in 1958 [9], ushered in the era of direct-acting antivirals (DAAs). Since then, many antiviral drugs and drug combinations have been successfully developed and marketed [10], which have largely mitigated many human viral pathogens that historically plagued human societies. Not surprisingly, most of these drugs target viruses that cause chronic infections and/or establish latency. Human immunodeficiency virus (HIV), in particular, has been at the center of antiviral drug development and drug regimen evolution, with dozens of single agents and fixed-dose combinations (FDCs) approved, spanning a wide range of compound classes and molecular targets [11, 12]. The everlasting needs to prevent infection, enhance drug accessibility, and improve adherence have also spurred developments in pre-exposure prophylaxis (PrEP) [13, 14], regimen simplification [15-17], and long-acting injectables (LAIs) [18-20]. Prior to HIV, the earliest antiviral drugs mostly targeted human herpesviruses (HHVs), including herpes simplex virus (HSV), varicella zoster virus (VZV), and human cytomegalovirus (HCMV). Other major chronic viruses targeted by various small-molecule antiviral drugs include hepatitis B virus (HBV) and hepatitis C virus (HCV), both causing viral hepatitis and increasing risk of hepatocarcinoma. Although current antiviral drugs typically do not clear HIV, HBV, or HHVs, the development of DAAs to successfully cure HCV represents a major breakthrough [21, 22] in antiviral therapy and provides hope that further development in antiviral drugs could eventually lead to the functional cure of other challenging viral infections. Widespread and seasonal acute viral infections, such as influenza virus, respiratory syncytia virus (RSV), and SARS-CoV-2, have also caused major mortality and morbidity, and have been targeted by successful and ongoing antiviral drug development efforts.

Antiviral Drugs Targeting Human Herpesviruses

HHVs, a family of eight large DNA viruses, are highly prevalent within human populations [23]. While primary infections are generally associated with low risk, these viruses are all capable of establishing lifelong latency. In immunocompromised individuals, the reactivation of the latent infection causes high morbidity and mortality. Among HHVs, ?-herpesviruses HSV and VZV, and ß-herpesvirus HCMV, have received particular attention in drug discovery.

The vast majority, if not all, of the earliest HHV drugs belonged to four distinct subclasses of nucleos(t)ide analogs (Table 1): (1) C-5 substituted thymidine analogs, including IDU [8, 24, 25], trifluridine (TFT) [26], and brivudine (BVDU) [27], where the C-5 substituent is mechanistically important by disrupting base pairing; (2) marine sponge tectitethya crypta spongonucleoside [28] vidarabine (ara-A) [29], which contains d-arabinose rather than d-ribose; (3) acyclic nucleosides [30] aciclovir (ACV), penciclovir (PCV), and ganciclovir (GCV); and (4) acyclic nucleoside phosphonate (ANP) [31] cidofovir. Intracellularly, all nucleoside analogs (the first three subclasses) are converted to monophosphate (MP) by a virally encoded kinase, and then further phosphorylated by cellular kinases to the active form triphosphate (TP). ANP cidofovir bypasses the function of viral kinase as the MP is already chemically installed, but still uses cellular kinases to form the active TP. Early mechanistic studies showed that these TPs can stop viral DNA synthesis via competitive viral polymerase inhibition or by getting incorporated into the DNA and acting as chain terminators. Of these nucleos(t)ide anti-herpes antiviral drugs, ACV [32, 33] is considered a milestone drug due to its excellent selectivity and low toxicity and has been used to effectively treat infections caused by most known HHVs, particularly HSV and VZV. Another acyclic nucleoside drug GCV [34, 35] has been the first-line treatment for HCMV for decades.

Table 1 Antiviral drugs against HHVs.

Drug class and MOA Drug name Note Year approved Indication approved Nucleos(t)ide analogs: phosphorylated intracellularly, incorporated and act as chain terminators Idoxuridine (IDU) Thymidine analog. 5-I blocking base paring. 1963 Topical treatment of herpes simplex keratitis Trifluridine (TFT) Thymidine analog. 5-CF3 blocking base paring 1980 Eye drops for treating keratitis and keratoconjunctivitis caused by HSV Brivudine (BVDU) Thymidine analog. 5-Bromovinyl blocking base paring 2000 Herpes zoster (VZV) in adult patients Vidarabine (ara-A) Marine spongonucleoside analog 1976 Ointment for treating HSV; herpes zoster (VZV) in AIDS patients Aciclovir (ACV) Acyclic nucleoside analog 1981 Treatment of HSV and VZV infections Penciclovir (PCV) Competitive viral pol inhibition and chain termination 1996 Treatment of zoster (VZV) and genital HSV Ganciclovir (GCV) Competitive viral pol inhibition and chain termination 1988 First-line treatment of CMV infections Cidofovir (CDV) Competitive viral pol inhibition and chain termination 1996 ACV-resistant HSV and GCV-resistant CMV infections Pyrophosphate mimic Foscarnet (PFA) Binding to the PPi binding site and blocking PPi release 1991 ACV-resistant HSV and VZV; GCV-resistant CMV infections Terminase inhibitor Letermovir (LTV) Targeting viral terminase component protein pUL56 2017 Prophylaxis of post-transplant HCMV Viral kinase inhibitor Maribavir (MBV) Inhibition of viral kinase (pUL97) 2021 Treating post-transplant HCMV infections resistant to other drugs Viral helicase-primase inhibitors Amenamevir (AMNV) Inhibition of viral helicase-primase complex 2017 Herpes zoster (shingles) Pritelivir (PTV) Inhibition of viral helicase-primase complex Phase 3 HSV infections in immunocompromised patients

Another mechanistically distinct viral polymerase inhibitor is the pyrophosphate (PPi) mimic foscarnet (PFA), which binds to a site similar to but distinct from the PPi binding site of the viral polymerase to block the pyrophosphate exchange [36]. Notably, PFA does not require phosphorylation and thus is kinase-independent.

Although polymerase-targeting nucleos(t)ide analogs and the PPi mimic PFA are largely effective against HHVs, they are limited by dose-related adverse effects and the emergence of drug resistance. In line with expanding the anti-herpes antiviral drug repertoire, efforts in recent years have led to the successful development of three mechanistically novel drug classes: amenamevir (AMNV) and pritelivir (PTV), inhibitors of viral helicase-primase complex, for treating VZV and HSV, respectively; letemovir (LTV), which targets pUL56, a component protein of the HCMV terminase complex, for HCMV prophylaxis post stem cell transplants; and maribavir (MBV), an HCMV kinase (pUL97) inhibitor for treating post-transplant HCMV resistant to other drugs.

Antiviral Drugs Targeting Human Immunodeficiency Virus

HIV drug discovery [37, 38] has been particularly successful with the approval of dozens of single agents in the past four decades (Table 2). These drugs, comprising a few distinct drug classes and mechanisms of action, coalesce to a large repertoire for effective antiretroviral therapy (ART), termed the highly active antiretroviral therapy (HAART) [39]. HAART regimens typically consist of two nucleoside reverse transcriptase inhibitors (NRTIs), along with an integrase inhibitor (INSTI), a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI).

Table 2 Antiviral drugs against HIV.

Drug class and MOA Drug name Note Year approved NRTIs: intracellularly phosphorylated, incorporated and act as obligate...