Letermovir and inhibitors of the terminase complex: a promising new class of investigational antiviral drugs against human cytomegalovirus

Abstract

Infection with cytomegalovirus is prevalent in immunosuppressed patients. In solid organ transplant and hematopoietic stem cell transplant recipients, cytomegalovirus infection is associated with high morbidity and preventable mortality. Prevention and treatment of cytomegalovirus with currently approved antiviral drugs is often associated with side effects that sometimes preclude their use. Moreover, cytomegalovirus has developed mutations that confer resistance to standard antiviral drugs. During the last decade, there have been calls to develop novel antiviral drugs that could provide better options for prevention and treatment of cytomegalovirus. Letermovir (AIC246) is a highly specific antiviral drug that is currently undergoing clinical development for the management of cytomegalovirus infection. It acts by inhibiting the viral terminase complex. Letermovir is highly potent in vitro and in vivo against cytomegalovirus. Because of a distinct mechanism of action, it does not exhibit cross-resistance with other antiviral drugs. It is predicted to be active against strains that are resistant to ganciclovir, foscarnet, and cidofovir. To date, early-phase clinical trials suggest a very low incidence of adverse effects. Herein, we present a comprehensive review on letermovir, from its postulated novel mechanism of action to the results of most recent clinical studies.

Identification of a short sequence in the HCMV terminase pUL56 essential for interaction with pUL89 subunit

“…The terminase complex is highly specific for HCMV, has no counterpart in the human organism, and thus represents a target of choice for new antivirals development. This has been confirmed by the recent development of letermovir in the transplant setting 3 , 4 .…”

A Native Human Monoclonal Antibody Targeting HCMV gB (AD-2 Site I)

“…Letermovir was approved in November 2017 for prevention of HCMV infection and disease in adult HSCT patients [33]. This non-nucleoside small molecule drug was developed in part to address the polymerase drug resistance issue by inhibiting a different viral target contributing to HCMV replication [34], namely, the terminase DNA packaging and cleavage complex, and in part to improve on the efficacy and toxicity profiles of the polymerase inhibitors [35]. Letermovir efficacy was established in a Phase 3 trial of seropositive recipients of HSCT ( N = 495 without detectable HCMV DNA at randomization) [36].…”

Hinge Region in DNA Packaging Terminase pUL15 of Herpes Simplex Virus: A Potential Allosteric Target for Antiviral Drugs

“…This is due to the fact that the molecular functions of the DNA packaging motor, capsid formation, DNA cleavage, and packaging of DNA into capsids, are virus-specific and not found in mammalian cells [30,31]. Current CMV terminase inhibitors include benzimidazoles and the 3,4-dihydro-quinazoline-4-yl-acetic acid derivative, letermovir [32].…”

“…Letermovir is believed to inhibit the viral terminase complex by targeting pUL56 because L241P, R369S, and C325Y mutations in pUL56 correlate with resistance to letermovir [31,42,43]. The inhibitory effect of letermovir is believed to be distinct due to the lack of cross-resistance of letermovir-resistant CMV strains to benzimidazoles [31,32]. While letermovir has no target-related toxicity, and has a good safety profile, it is specific for human CMV and is ineffective against other viruses, including the remaining herpesviruses [44].…”