New vaccines and antiviral drugs for cytomegalovirus

2020

IJMS

Cytomegalovirus (CMV) is one of the major human health threats worldwide, especially for immunologically comprised patients. CMV may cause opportunistic infections, congenital infections, and brain diseases (e.g., mental retardation and glioblastoma). The etiology of brain diseases associated with human CMV (HCMV) infections is usually complex and it is particularly difficult to treat because HCMV has a life-long infection in its hosts, high mutation rate, and latent infections. Moreover, it is almost impossible to eradicate latent viruses in humans. Although there has been progress in drug discovery recently, current drugs used for treating active CMV infections are still limited in efficacy due to side effects, toxicity, and viral resistance. Fortunately, letermovir which targets the HCMV terminase complex rather than DNA polymerase with fewer adverse reactions has been approved to treat CMV infections in humans. The researchers are focusing on developing approaches against both productive and latent infections of CMV. The gene or RNA targeting approaches including the external guide sequences (EGSs)-RNase, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and transcription activator-like effector nucleases (TALENs) are being investigated to remove acute and/or latent CMV infections. For the treatment of glioblastoma, vaccine therapy through targeting specific CMV antigens has improved patients’ survival outcomes significantly and immunotherapy has also emerged as an alternative modality. The advanced research for developing anti-CMV agents and approaches is promising to obtain significant outcomes and expecting to have a great impact on the therapy of brain diseases associated with CMV infections.

Section: Medicationmentioning

confidence: 99%

Potential Therapeutic Approaches Against Brain Diseases Associated with Cytomegalovirus Infections

Wang

2020

IJMS

“…Letermovir has been approved for the prophylaxis of CMV infections in patients. Several new drugs were developed but still failed in the phase III and more clinical trials would be needed, including maribavir and brincidofovir [37]. Valnoctamide, a neuroactive mood stabilizer which inhibits CMV infection in the developing brain and attenuates neurobehavioral dysfunctions, was shown to have anti-CMV potential [38].…”

Section: Anti-viral Drugsmentioning

confidence: 99%

Antiviral Agents as Therapeutic Strategies Against Cytomegalovirus Infections

Wang

2019

Viruses

Cytomegalovirus (CMV) is a threat to human health in the world, particularly for immunologically weak patients. CMV may cause opportunistic infections, congenital infections and central nervous system infections. CMV infections are difficult to treat due to their specific life cycles, mutation, and latency characteristic. Despite recent advances, current drugs used for treating active CMV infections are limited in their efficacy, and the eradication of latent infections is impossible. Current antiviral agents which target the UL54 DNA polymerase are restricted because of nephrotoxicity and viral resistance. CMV also cannot be prevented or eliminated with a vaccine. Fortunately, letermovir which targets the human CMV (HCMV) terminase complex has been recently approved to treat CMV infections in humans. The growing point is developing antiviral agents against both lytically and latently infected cells. The nucleic acid-based therapeutic approaches including the external guide sequences (EGSs)-RNase, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and transcription activator-like effector nucleases (TALENs) are being explored to remove acute and/or latent CMV infections. HCMV vaccine is being developed for prophylaxis. Additionally, adoptive T cell therapy (ACT) has been experimentally used to combate drug-resistant and recurrent CMV in patients after cell and/or organ transplantation. Developing antiviral agents is promising in this area to obtain fruitful outcomes and to have a great impact on humans for the therapy of CMV infections.

“…Ganciclovir (GCV) and its orally bioavailable prodrug, Valganciclovir, have served as gold standards for pre-emptive therapy and prophylaxis against HCMV in solid organ transplant patients [ 6 ] as well as for the treatment of CMV retinitis [ 7 ] for almost 30 years. However, their myelosuppressive potential precludes their prophylactic use in stem cell transplant recipients, which has led to their administration, mostly upon engraftment [ 8 ]. In addition, mutations mapping in the gene encoding for the UL97 kinase (responsible for the first phosphorylation of GCV towards its active triphosphate form) and in the UL54 gene encoding for the DNA polymerase (target of ganciclovir triphosphate), have led to the emergence of drug resistant strains [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of New Imidazopyridine Nucleoside Derivatives Designed as Maribavir Analogues

et al. 2020

The strong inhibition of Human Cytomegalovirus (HCMV) replication by benzimidazole nucleosides, like Triciribine and Maribavir, has prompted us to expand the structure–activity relationships of the benzimidazole series, using as a central core the imidazo[4,5-b]pyridine scaffold. We have thus synthesized a number of novel amino substituted imidazopyridine nucleoside derivatives, which can be considered as 4-(or 7)-aza-d-isosters of Maribavir and have evaluated their potential antiviral activity. The target compounds were synthesized upon glycosylation of suitably substituted 2-aminoimidazopyridines, which were prepared in six steps starting from 2-amino-6-chloropyridine. Even if the new compounds possessed only a slight structural modification when compared to the original drug, they were not endowed with interesting antiviral activity. Even so, three derivatives showed promising cytotoxic potential.