Figure 1. HCMV structure and entry into host cells. HCMV glycoproteins gH, gL, UL128, UL130 and UL131 assemble together to form a functional complex for binding to host cellular receptors, such as gH/gL/UL128- 131 receptors and gH/gL/gO receptors. gH/gL/UL128-131 mediates entry into epithelial/endothelial cells and gH/gL/gO mediates entry into fibroblasts.

Figure 1. HCMV structure and entry into host cells. HCMV glycoproteins gH, gL, UL128, UL130 and UL131 assemble together to form a functional complex for binding to host cellular receptors, such as gH/gL/UL128- 131 receptors and gH/gL/gO receptors. gH/gL/UL128-131 mediates entry into epithelial/endothelial cells and gH/gL/gO mediates entry into fibroblasts.

Figure 2. A feasible process using different strategies for the effective treatment of HCMV infections.

Table 1. Major strategies have been used clinically or potential for the treatment of HCMV infections.

Table 1. Major strategies have been used clinically or potential for the treatment of HCMV infections.

StrategyAdoptionCurrent StatusMain ProblemAntiviral drugsTraditional: ganciclovir, valganciclovir, cidofovir, foscarnet
Novel: letermovir, maribavirExtensively used clinically for the treatment of acute infectionsSide effects, toxicity, resistance issues including drug resistance and cross resistanceNucleic acid-based gene targeting approachEGSs-RNase, CRISPRs/Cas9, TALENsOnly under study for basic research, not for clinical application so farOption of delivery tool, safety concernsCell therapyACT, immunotherapyNot universal, only used conditionally in limited patient population or special casesEfficacy evaluation is difficult, Random controlled clinical trials and prognosis manifestation is still lacking

Table 2. Traditional antiviral drugs approved for the treatment of HCMV acute infections.

Table 2. Traditional antiviral drugs approved for the treatment of HCMV acute infections.

DrugStructureMechanismMain Side EffectsGanciclovirA synthetic analogue of 2′-deoxy-guanosineViral UL54 DNA polymerase inhibitorA potential carcinogen, granulocytopenia, neutropenia, anemia, thrombocytopeniaValganciclovirL-valyl ester of ganciclovirViral UL54 DNA polymerase inhibitorA potential carcinogen, granulocytopenia, neutropenia, anemia, thrombocytopeniaCidofovirA monophosphate nucleotide analogueViral UL54 DNA polymerase inhibitorNephrotoxicity, neutropenia, nausea, uveitis, iritis, asthenia, alopecia, ocular hypotonyFoscarnetPyrophosphate analogue, a structural mimic of the anion pyrophosphateInhibitor of the pyrophosphate- binding site on viral DNA polymerase (or reverse transcriptase); Noncompetitive inhibitor of many RNA and UL54 DNA polymeraseNephrotoxicity, electrolyte disturbance, genital ulceration, paranesthesia, irritability, hallucination

Table 3. Novel drugs have been approved or being developed for the treatment of HCMV infections.

Table 3. Novel drugs have been approved or being developed for the treatment of HCMV infections.

DrugStructureMechanismMain Side EffectsCurrent StatusReferenceLetermovirA non-nucleoside, 3,4-dihydroquinazolinyl acetic acidViral terminase complex inhibitor encoded by gene UL56, UL51, UL89Nausea, diarrhea, vomiting, swelling in arms and legs, cough, headache, tiredness, hepatitis, stomach painApproved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2017[71,72,73,74,75,76]MaribavirA benzimidazole ribosideViral protein kinase (UL97) inhibitorTaste disturbance, nausea, diarrhea, vomiting and fatigueApproved by USA FDA in 2021[77,78,79,80]BrincidofovirAn alkoxyalkyl ester prodrug containing the synthetic, acyclic nucleoside monophosphate analog cidofovirViral UL54 DNA polymerase inhibitorDiarrhea, nausea, vomiting, and abdominal pain and others (under study)Under clinical trial[76,81,82,83]FilociclovirA guanosine nucleoside analogViral UL54 DNA polymerase and the UL97 kinase inhibitorMild to extreme stomach upset, headaches, mild fever and others (under study)Under clinical trial[84,85,86]ValnoctamideA structural isomer of valpromide, a valproic acid prodrugInhibition of viral attachment to the host cellSommolence, the slight motor impairments and others (under study)Under study[87,88]