Effects of chloroquine on viral infections: an old drug against today's diseases

Abstract: Personal view Antiviral effects of chloroquine Effects of chloroquine on viral infections: an old drug against today’s diseases? Andrea Savarino, Johan R Boelaert, Antonio Cassone, Giancarlo Majori, and Roberto Cauda. Chloroquine is a 9-aminoquinoline known since 1934. Apart from its well-known antimalarial effects, the drug has interesting biochemical properties that might be applied against some viral infections. Chloroquine exerts direct antiviral effects, inhibiting pH-dependent steps of the replication of several viruses including members of the flaviviruses, retroviruses, and coronaviruses. Its best-studied effects are those against HIV replication, which are being tested in clinical trials. Moreover, chloroquine has immunomodulatory effects, suppressing the production/release of tumour necrosis factor
and interleukin 6, which mediate the inflammatory complications of several viral diseases. We review the available information on the effects of chloroquine on viral infections, raising the question of whether this old drug may experience a revival in the clinical management of viral diseases such as AIDS and severe acute respiratory syndrome, which afflict mankind in the era of globalisation. Endocytosis of viral particles Transport of endocytosed virus Virus uncoating Replication/ transcription of viral nucleic acids Post-translational processing of envelope glycoproteins in the Golgi Transport of envelope components Assembly/ budding Lancet Infect Dis 2003; 3: 722–27 Chloroquine is a 9-aminoquinoline that has been known since 1934. Specifically synthesised to be used as an antimalarial agent, chloroquine was subsequently shown to have immunomodulatory properties that have encouraged its application in the treatment of autoimmune diseases such as rheumatoid arthritis. For this specific pathology, chloroquine and its hydroxy-analogue hydroxychloroquine have represented a valid contribution to the available pharmacological tools, since they proved able to slow down the progress of the disease while showing limited toxicity.1 Unfortunately, chloroquine is being gradually dismissed from antimalarial therapy and prophylaxis, due to the continuous emergence of chloroquine-resistant Plasmodium falciparum strains. However, the tolerability, low cost, and immunomodulatory properties of chloroquine/hydroxychloroquine are associated with biochemical effects that suggest a potential use in viral infections, some of whose symptoms may result from the inflammatory response.2,3 We raise the question of whether this old drug whose parent compound, quinine, was isolated in the late 19th century from the bark of the tropical cinchona tree, may experience a revival in the clinical management of viral diseases of the era of globalisation. General biochemical and cellular effects of chloroquine Both chloroquine and hydroxychloroquine are weak bases that are known to affect acid vesicles leading to dysfunction of several enzymes. Extracellularly, chloroquine/hydroxychloroquine is present mostly in a protonated form that, due 722 Transport of newly formed viral particles Assembly/budding Exocytosis of viral particles Figure 1. Steps of the replication of different viruses affected by chloroquine (marked by red rectangles). Chloroquine inhibits the replication of different viruses either at the early or late stages of viral replication. to its positive charge, is incapable of crossing the plasma membrane. However, the non-protonated..