Coronavirus In Infections - I Pl Perjsi, PhD University of Pcs - - PowerPoint PPT Presentation

Medicinal Chemistry ry of f Coronavirus In Infections - I

Pál Perjési, PhD University of Pécs Institute of Pharmaceutical Chemistry May 05, 2020

The Coronavirus pandemic (M (May 5, , 2020) https://coronavirus.jhu.edu/map.h .html

The Coronavirus pandemic

https://www.worldometers.info/coronavirus/?utm_campaign=h

• meAdvegas1?

The structure of the viruses

• Viruses

are the smallest parasites, typically ranging from 0.02 to 0.4 micrometer, although several very large viruses up to 1 micrometer long (megavirus, pandoravirus) have recently been discovered.

• Viruses

depend completely

• n

cells (bacterial, plant,

• r

animal) to reproduce.

• Viruses (virions) have an outer cover of protein (capsid) and sometimes lipid

(envelope), an RNA or DNA core, and sometimes enzymes needed for the first steps of viral replication.

The size of the viruses

SIB Swiss Institute of Bioinformatics (www.sib.swiss)

Classification of Viruses

DNA viruses

• Contain an DNA genome
• Virus replication:
• DNA-depndent DNA

polymerase

• Examples:
• Herpes Virus
• Hepatitis B virus
• Epstein-Barr virus

RNA Viruses

• Contain an RNA genome.
• Virus replication:
• RNA-dependent RNA polymerase
• Reverse transcriptase (Retroviruses)
• Examples:
• Rubella virus
• Dengue fever virus
• Hepatitis A virus
• Hepatitis C virus
• HIV
• Influenza virus
• Coronavirus

Classification of Viruses The Baltimore Scheme

https://open.oregonstate.education/generalmicrobiology/chapter/the-viruses/

Replication of f the double stranded DNA vir iruses – Replication of f the genom

DNA base pairing:

Key enzymes involved:

• 1. Helicase
• 2. DNA dependent DNA polymerase

Double-stranded DNA viruses usually must enter the host nucleus before they are able to replicate. Some of these viruses require host cell polymerases to replicate their genome, while others, such as adenoviruses or herpes viruses, encode their own replication factors. Most prominently, DNA-dependent DNA-polymerase synthesizes the new strands by adding nucleotides that complement each (template) strand. Polyomaviruses, adenoviruses, and herpesviruses are all nuclear-replicating DNA viruses.

https://open.oregonstate.education/generalmicrobiology/ch apter/the-viruses/

Replication of f the double stranded DNA vir iruses - Transcription

DNA-RNA base pairing:

Transcription is the first step in gene expression.It involves copying a gene's DNA sequence to make an RNA molecule. Transcription is performed by enzymes called DNA-dependent RNA polymerases, which link nucleotides to form an RNA strand (using a DNA strand as a template). In viruses and bacteria, the RNA transcripts act as messenger RNAs (mRNAs) right away.

https://open.oregonstate.education/generalmicrobiology/ chapter/the-viruses//

Replication of f the dsRNA vir iruses

• Double-stranded

RNA viruses, such as the rotavirus, cause diarrheal illness in humans.

• Cells have systems to destroy any

dsRNA found in the cell. Thus the viral genome, in its dsRNA form, must be hidden or protected from the cell enzymes.

• Cells lack RNA-dependent RNA-polymerases, necessary for replication of the viral genome so

the virus must have this enzyme itself. The viral RNA-dependent RNA polymerase acts as both a transcriptase to transcribe mRNA, as well as a replicase to replicate the RNA genome.

Replication of f the (+ (+) sense ssRNA vir iruses

• Viruses with plus-strand RNA, such as

coronaviruses (CoVs), can use their genome directly as mRNA with translation by the host ribosome

• ccurring as soon as the unsegmented

viral genome gains entry into the cell.

• One of the viral genes expressed yields

an RNA-dependent RNA-polymerase (or RNA replicase), which creates minus- strand RNA from the plus-strand genome.

• The minus-strand RNA can be used as a template for more plus-strand RNA, which can

be used as mRNA or as genomes for the newly forming viruses.

Negative-sense sin ingle-stranded RNA vir iruses ((-)ssRNA vir iruses)

• Negative sense ssRNA viruses, such

as the Ebola virus and the influenza virus, need an RNA dependent RNA polymerase (RNA replicase) within its capside to form a positive sense RNA.

• The positive-sense RNA acts as a

viral mRNA, which is translated into proteins for the production of new virion materials.

• When viral genomes are needed the

plus-strand RNAs are used as templates to make minus-strand RNA.

Replication of f the (+ (+) sense ssRNA vir iruses – Retroviruses -I

• Despite the fact that the retroviral

genome is composed of +ssRNA, it is not used as mRNA.

• Instead, the virus uses its RNA

dependent DNA polymerase (reverse transcriptase) to synthesize a piece of ssDNA complementary to the viral genome.

• Because RNA transcription does not involve the same error-checking

mechanisms as DNA transcription, RNA viruses, particularly retroviruses, are particularly prone to mutation.

Replication of f the (+ (+) sense ss ssRNA vir iruses – Retroviruses-II II

• Lastly,

the reverse transcriptase is used as a DNA polymerase to make a complementary copy to the ssDNA, yielding a dsDNA molecule.

• This allows the virus to insert

its genome, in a dsDNA form, into the host chromosome, forming a provirus.

• A provirus can remain latent indefinitely or cause the expression of viral genes, leading

to the production of new viruses. Excision of the provirus does not occur for gene

• expression. (e.g. HIV; human T-lymphotropic virus type 1 and 2 (HTLV-1 and HTLV-2))

Coronaviridae

• Coronaviruses are involved in human

and vertebrate's diseases. Coronaviruses are members of the subfamily Orthocoronavirinae in the family Coronaviridae and the order Nidovirales

The particles are typically decorated with large (appr. 20 nm), club- or petal-shaped surface projections (the "peplomers" or "spikes"), which in electron micrographs of spherical particles create an image reminiscent of the solar corona.

Taxonomy of Coronaviridae

(according to the International Committee on Taxonomy of Viruses)

https://www.mdpi.com/2076-0817/9/3/186/htm

Origin of evolution of human-pathogen Coronaviruses

https://www.mdpi.com/2076-0817/9/3/186/htm SARS: Severe Acute Respiratory Syndrome MARS: Middle East Respiratory Syndrome 2002 2012 2019

COVID-19 (SARS-CoV-2)

• COVID-19

is a spherical

• r

pleomorphic enveloped particles containing single-stranded (positive-sense) RNA associated with a nucleoprotein (N) within a capsid comprised

• f

matrix protein. The envelope bears club-shaped glycoprotein (S)

• projections. Some coronaviruses

also contain a hem agglutinin- esterase protein (HE)4.

https://doi.org/10.1016/j.jmii.2020.03.022

REPLICATION OF COVID19

• 1. Attachment of the virus to receptors on

the host cell surface;

• 2. Entry of the virus through the host cell

membrane;

• 3. Uncoating of viral nucleic acid;
• 4. Replication

Synthesis of early regulatory proteins, eg, nucleic acid polymerases; Synthesis of new viral RNA or DNA; Synthesis of late, structural proteins

• 5. Assembly (maturation) of viral particles;
• 6. Release from the cell

Potential anti-viral therapeutics used in patients with SARS and MERS infections

The role of replication process in pathogenicity

• SARS-CoV-2 (COVID-19) binds to

ACE2 (the angiotensin- converting enzyme 2) by its S (Spike) protein and allows COVID-19 to enter and infect cells.

• In order to attach the virus

receptor (spike protein) to its cellular ligand (ACE2), activation by the serine protease TMPRSS2 is needed.

https://doi.org/10.1016/j.jmii.2020.03.022

In Inhibition of f TMPRSS2 by by Camostat Mesylate (N (NI-03)

Thank you for your attention!