Anti-Hcv

Background


"Hepatitis" means inflammation of the liver. And the most common types are Hepatitis A, Hepatitis B and Hepatitis C. Hepatitis C virus (HCV) is classified within the genus hepacivirus, and belongs to the family flaviviridae. The genome of the virus is ∼9.6 kb long and contains a long open reading frame, flanked by untranslated 5' and 3' sequences.The 5' UTR sequence contains 341 nt located upstream of the open reading frame (ORF) translation initiation codon. The 5' UTR contains four highly structured domains, numbered I to IV, containing numerous stem-loops and a pseudoknot. Domains II, III and IV together with the first 12 to 30 nt of the core-coding region constitute the internal ribosome entry site (IRES). The HCV IRES can form a stable preinitiation complex by directly binding the 40S ribosomal subunit without the need of canonical translation initiation factors, and thus plays an important role in initiation of HCV polyprotein translation. The 3' UTR of HCV contains approximately 225 nt. It is organized into three regions, from 5' to 3' a variable region of approximately 30–40 nt, a long poly(U)-poly(U/UC) tract, and a highly conserved 3'-terminal stretch of 98 nt (X region). The 3' UTR interacts with the NS5B RNAdependent RNA polymerase (RdRp). The 3' X region and the 52 upstream nt of the poly(U/C) tract were found to be essential for RNA replication. However, about 20% of HCV infections are spontaneously cleared within six months after the initial infection, which is termed as acute infection. The strong and specific cytotoxic T cells (CD8+) response observed in acute HCV infection is correlated with the control of viremia and is very likely the reason for acute liver damage. The remaining 80% of HCV infections are not cleared by the host immune system and these patients become chronically infected. In a timeframe of 10–40 years, these patients may progressively develop chronic hepatitis, steatosis and fibrosis, and 20% of them will progress to the end stage: liver cirrhosis. Each year, 5% of those with cirrhosis develop hepatocellular carcinoma (HCC). Chronic hepatitis is the inflammation of the liver characterized by the infiltration of immune cells into the liver after the host immune system fails to control viral replication during the acute phase. Steatosis is the production and accumulation of excessive fatty acids in liver cells, and it is observed in more than half of chronic HCV patients. Patients with chronic hepatitis and/or steatosis are at high risk of developing fibrosis, cirrhosis, and hepatocellular carcinoma. Many factors contribute to the stepwise development of liver diseases in chronic HCV patients. Besides risk factors like age, ethnicity, sex, co-infection with hepatitis B virus or human immunodeficiency virus type 1 (HIV-1) and host genetics, e.g., IL-28B gene variants, direct effects of HCV proteins and indirect impact of infiltrated immune cells are the two most important contributors to the disease progression.

Hepatitis C virus infection and replication-potential therapeutic targets

Generally, the HCV life cycle can be divided into the following stages: attachment, entry and fusion, translation and replication, assembly and secretion. First, the attachment of virus to host cell is mediated by glycosaminoglycans (GAGs, e.g., heparin sulfate) and the low density lipoprotein receptor (LDLR). Next, specific interactions between the viral glycoprotein E2 and cellular receptors induce receptormediated endocytosis. This “entry” step has been intensively studied and four HCV entry receptors/ co-receptors have been discovered. The first one is a tetraspanin protein, CD81, which was discovered by screening for HCV E2-interacting proteins. The scavenger receptor class B type 1 (SR-B1) was subsequently found to also interact with HCV E2 and to play a role in HCV entry. SR-B1 normally functions as a LDL/HDL receptor and is highly expressed in the liver and other steoidogenic tissues. Recently, two tight junction (TJ) proteins, claudin-1 (CLDN1) and occluding (OCLN) were discovered to confer susceptibility to HCV infection in human embryonic kidney cell line 293T and mouse embryonic kidney fibroblast cell line NIH3T3, respectively, even though they were not found to directly bind HCV envelope proteins. The current HCV cell entry model suggests roles of CD81 and SR-B1 in the early entry step and roles of CLDN1 and OCLN in the late entry steps. After attachment, HCV E2 interacts with cellular receptors CD81 and SR-B1, and their interaction triggers signaling cascades essential for entry and downstream events. The virus is then transferred to CLDN1 and OCLN via CLDN1's association with CD81 and internalized by endocytosis, followed by pH-dependent fusion. Interestingly, none of these four receptors are exclusively expressed in the liver, the primary target of HCV. Nevertheless, restrictions on steps other than entry can also shape the liver tropism of HCV, such as the requirement of liver-specific microRNA miR122 for HCV replication. Thus, it is possible that only human hepatocytes express all the cellular factors required for a complete HCV life cycle.

Chemical biology offers a wide range of small molecules, which are used as chemical probes for studying DNA, RNA, and proteins. Their scaffolds range from naturally occurring molecules containing carbohydrate and peptide moieties to molecules having incorporated unnatural amino acids. Small molecule probes are especially useful in understanding protein function, in living systems, as they allow fast and reversible modulation of individual protein domains without affecting the whole protein. Their effect can be controlled by varying probe concentration and treatment time. Small molecule probes have an advantage over using genetic approaches such as RNAi (RNA interference) because these silence the gene encoding protein and cause the loss of the whole proteins function. There are numerous examples of small molecules used for selectively modulating protein function. One such is the small molecule rapamycin, which specifically blocks one of TOR protein functions. Small molecule probes can be used in several ways to inhibit the HCV viral life cycle. Small molecules can: directly target the HCV proteins; affect the host proteins involved in HCV replication; modulate the host metabolic pathways; stimulate the immune system; or directly inhibit replicating RNA.

As for trearment, it varies based on which type of HCV cause it.

HCV genotypes I: ledipasvir, sofosbuvir, boceprevir, paritaprevir, ombitasvir, dasabuvir and ribavirin, faldaprevir

HCV genotypes II: sofosbuvir, ribavirin

HCV genotypes III: sofosbuvir, ribavirin, daclatasvir and pegylated interferon

HCV genotypes IV: ledipasvir, sofosbuvir, paritaprevir, ritonavir and ribavirin

HCV genotypes V and HCV genotypes VI: sofosbuvir and ledipasvir

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