Arenavirus

What is Arenavirus?

Arenaviruses belong to the Arenaviridae family, which is an enveloped, segmented, single-stranded negative-strand RNA virus (sNSV). It is shaped like a grain of sand, so it is named a seed-grained virus, which is a small branch of the virus. Thirteen species of arenaviruses have been discovered, of which 4 are pathogenic to humans. Among them, all the arenaviruses that are known to cause disease in humans belong to the genus Mammalian arenaviruses, typically represented by Lassa virus (LASV).

Arenavirus structure

Arenaviridae belong to the family Arenaviridae, and the virus particles are morphologically varied, ranging from round to pleomorphic, with a diameter of 50-300 nanometers, and an envelope with a T spike on the surface of the envelope. The viral genome consists of two fragments of single strands of negative RNA: large (L) and small (S) fragments. The 5' and 3' ends of these two fragments are inversely complemented by 17-30 nucleotide non-coding regions (NURs) to form a handle structure.

L RNA fragment: Approximately 7.2 kb encodes a viral RNA-dependent RNase (L protein) and a zinc-binding matrix protein (Z protein) via a dual coding strategy, respectively. The L protein is an enzyme that transcribs and copies the viral genome, and the Z protein forms a small zinc finger structure that facilitates viral budding and assembly.

S RNA fragment: About 3.5 kb, it also encodes the viral nucleocapsid protein (N protein) and the envelope glycoprotein precursor (GPC protein) by a dual coding strategy, respectively. The GPC protein is hydrolyzed in the Golgi apparatus to mature viral envelope glycoproteins GP1, GP2 and signal peptide (ssp). GP1 binds to viral receptors, and GP2 is a transmembrane protein that regulates the fusion of viruses with cells.

Each fragment has two open reading frames (ORFs), each of which is separated by an intergenic non-coding region (IGR) that forms the stem-loop structure. The functions of IGR mainly include structure-dependent transcriptional termination and viral assembly and budding.

Fig.1 Map of the pattern of the granulovirus particles and the genome structure of the RNA fragment. (Radoshitzky Sheli R., et al., 2015)

Arenavirus replication

The main cell surface receptor into which LASV enters is stromal glycan, an extended oligosaccharide located on the widely distributed peripheral membrane protein alpha-triosan. After binding, LASV virions are internalized by endocytosis. GPC responds to the acidic endosomal environment by undergoing a conformational shift known as GPC priming, which causes it to dissociate from α-DG. Primed GPC binds to the endosomal receptor lysosome-associated membrane protein 1 (LAMP1). Upon binding to LAMP1, the conformation of GPC changes, which mediates viral fusion with endosomal membranes and the release of LASV genome fragments into the cytoplasm.

The endonuclease activity of the L protein cleaves the 5' end of the cellular mRNA and then utilizes the negative sense portion of the small genomic fragment and the large genomic fragment as a template for the synthesis of the transcribed mRNA. Together, the newly synthesized NP and L proteins are able to synthesize complementary strands of genomic fragments known as antigenomes through RNA-dependent RNA polymerization. The anti-genome then serves as a template for the mRNA encoding the GPC precursor and the Z protein. The anti-genome can also serve as a template for generating more genomic fragments that are integrated into future virions.

Fig.2 LASV structure, genome organization, and replication strategy. (Garry Robert F., 2023)

Since the replication of arenaviruses mainly relies on the viral polymerase synthesized by the virus itself, this molecular machine is more conserved among all arenaviruses, and the host cell basically does not have the same functional proteins. Therefore, drugs targeting viral polymerases are expected to achieve good specificity. Revealing the working mechanism of arenavirus L protein and the molecular mechanism of its interaction with the Z protein is of great significance for a comprehensive understanding of the replication mechanism of arenavirus, and will also provide new guidance for the prevention and treatment of arenavirus infection-related diseases.

Arenavirus treatment

Pharmacotherapy

Favipiravir (T-705): A small molecule purine analogue that has shown advantages over the traditional drug ribavirin in the treatment of Lassa virus (LASV) infection in multiple animal models. Favipiravir exhibits potent antiviral activity by inhibiting RNA polymerase, thereby preventing viral replication. While its performance in animal models has been encouraging, there have been some challenges in clinical practice. In a clinical trial, two patients with Lassa fever were treated with a combination of Fapiravir and ribavirin and survived. However, the researchers found that viral RNA was detected in the blood and semen of these patients for a long time, suggesting that there may be latent or low levels of persistent infection with the virus. This discovery raises new research topics for the long-term efficacy of drugs and the complete elimination of the virus.

ST-193: A new viral entry inhibitor specifically targets the Lassa virus envelope glycoprotein, preventing the virus from entering host cells. In Phase i human clinical trials, ST-193 was shown to be safe with no serious side effects. The mechanism of action of the drug is to effectively inhibit the infection process of the virus by binding and neutralizing the glycoprotein on the virus envelope, and prevent the virus from fusing with the host cell membrane. The development of ST-193 provides new ideas for the treatment of Lassa virus infections, especially strains that are resistant to other antiviral drugs.

LHF-535: Another viral entry inhibitor of Lassa virus, the mechanism is similar to ST-193 in that it also inhibits viral entry by targeting the virus's envelope glycoprotein. In Phase i human clinical trials, LHF-535 was shown to be safe, well tolerated and potentially effective. LHF-535 is characterized by highly effective viral entry inhibition, making it a strong candidate for the treatment of Lassa fever. Studies have shown that LHF-535 can effectively prevent the virus from entering host cells, thereby reducing the spread and replication of the virus in the body, providing better treatment results for patients.

Vaccine

There is currently no approved LASV vaccine. However, several vaccine platforms have been developed that have shown efficacy in animal models, some of which have recently entered Phase I human clinical trials. Among the platforms that have been evaluated as potential LASV vaccines are ML29 MOPV/LASV live recombinant agent, a DNA vaccine and recombinant vesicular stomatitis virus, rabies virus, measles virus, vaccinia virus, and adenovirus vector vaccines. Other vaccine candidates include LASV virus-like particles and viral replicon particle vaccines.

Hemorrhagic fevers, caused by non-viral causes, are one of the most devastating emerging diseases in humans.

Summary

Arenaviruses have become a great public health threat and can cause severe hemorrhagic fever and neurological disease in humans and other animals. These viruses encode a large multidomain RNA-dependent RNA polymerase for transcription and replication of viral genomes. Due to the current lack of licensed vaccines and limited treatment options, the development of effective small molecule drugs against Ana virus is a top priority. Pharmacologists have identified several broadly active, potent, and broadly active arenavirus cell entry inhibitors that are effective against major hemorrhagic arenaviruses through high-throughput screening of small molecule libraries.

BOC Sciences offers a variety of potent and broadly active arenavirus cell entry inhibitors that are effective against major hemorrhagic arenaviruses.

References

• Radoshitzky, Sheli R., et al., Past, present, and future of arenavirus taxonomy. Arch Virol (2015): 1851-1874.
• Garry, Robert F., Lassa fever—the road ahead. Nature Reviews Microbiology 21.2 (2023): 87-96.

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