HPO Lecture CHEM1101 2021 Nitsche 2 PDF

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CHEM1101 – Chemistry HPO - Biological Chemistry

Antiviral drug discovery Christoph Nitsche Research School of Chemistry Room 3.06 [email protected]

Antiviral drugs against HIV

0.15% (GER)

0.17% 18.9% (SA)

2017: 36.9 million people living with HIV http://http://www.who.int/gho/hiv/en/

https://www.wikipedia.org

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Antiviral drugs against HIV

2017: 21.7 million (59%)

http://www.who.int/gho/hiv/data/en/

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Antiviral drugs against HIV

Graham L. Patrick, An Introduction to Medicinal Chemistry, 5th edition, 2013, Oxford University Press. ©

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Resistance • Reverse transcriptase error rate: 1/10000 • 108-109 replication cycles per day à 105 point mutations per day in one patient

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Reverse transcriptase

PDB code: 3KLF (HIV-1 reverse transcriptase in complex with double-stranded DNA)

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Reverse transcriptase inhibitors • RT is unique to retroviruses • cellular DNA polymerases may also be inhibited (selectivity) • Nucleoside reverse transcriptase inhibitors (NRTIs) • Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Graham L. Patrick, An Introduction to Medicinal Chemistry, 5th edition, 2013, Oxford University Press. ©

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Examples of NRTIs

Zidovudine

What do they have all in common? Chain terminators (polymerase synthesises DNA from 5’ to 3’) Graham L. Patrick, An Introduction to Medicinal Chemistry, 5th edition, 2013, Oxford University Press. ©

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Examples of NRTIs

Zidovudine (triphosphate)

PDB code: 3V4I (HIV-1 reverse transcriptase in complex with double-stranded DNA and zidovudine triphosphate)

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Examples of NNRTIs (allosteric)

Graham L. Patrick, An Introduction to Medicinal Chemistry, 5th edition, 2013, Oxford University Press. ©

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Examples of NNRTIs (nevirapine)

Nevirapine

PDB code: 3V81 (HIV-1 reverse transcriptase in complex with double-stranded DNA and nevirapine)

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HIV Protease Symmetrical dimer made up of two identical protein units (99 amino acids each)

Graham L. Patrick, An Introduction to Medicinal Chemistry, 5th edition, 2013, Oxford University Press. ©

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HIV Protease

PDB code: 1KJF (inactive variant D25N)

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HIV Protease

Graham L. Patrick, An Introduction to Medicinal Chemistry, 5th edition, 2013, Oxford University Press. ©

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HIV Protease

PDB code: 1KJF (inactive variant D25N bound to substrate RPGNFLQSRP)

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HIV Protease (aspartyl protease)

Transition state Graham L. Patrick, An Introduction to Medicinal Chemistry, 5th edition, 2013, Oxford University Press. ©

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Transition state isosteres (Asp proteases)

Pepstatin

Graham L. Patrick, An Introduction to Medicinal Chemistry, 5th edition, 2013, Oxford University Press. ©

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HIV protease inhibitors

Graham L. Patrick, An Introduction to Medicinal Chemistry, 5th edition, 2013, Oxford University Press. ©

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Saquinavir

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poor oral bioavailability: high molecular weight peptidic character

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susceptibility to drug resistance Graham L. Patrick, An Introduction to Medicinal Chemistry, 5th edition, 2013, Oxford University Press. ©

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Ritonavir and Iopinavir (de novo design)

Graham L. Patrick, An Introduction to Medicinal Chemistry, 5th edition, 2013, Oxford University Press. ©

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Ritonavir and Iopinavir

X-ray crystal structure: NH groups of the inhibitor bind to Gly-27 and Gly-27’, but are too close to each other to allow optimal hydrogen bonding à Design of new inhibitors with an extra bond to separate the NH groups

Graham L. Patrick, An Introduction to Medicinal Chemistry, 5th edition, 2013, Oxford University Press. ©

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Ritonavir and Iopinavir

Approach led to compounds of higher affinity Increased separation of amide NHs failed to improve the geometry of the hydrogen bonding interactions with Gly-27 and Gly-27’ Improved activity was caused by reasons other than the proposed Graham L. Patrick, An Introduction to Medicinal Chemistry, 5th edition, 2013, Oxford University Press. ©

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Ritonavir and Iopinavir

Interaction with Val82

V82A mutation causes resistance against ritonavir (loss of P3 interaction) Lopinavir has enhanced interaction with the S2 subsite, balancing out the loss of binding due to the removal of the P3 group. Graham L. Patrick, An Introduction to Medicinal Chemistry, 5th edition, 2013, Oxford University Press. ©

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SARS-CoV-2 SARS-CoV-2 replication mechanism Coronaviruses engage with a host cell-surface receptor and deposit their RNA genomes into the host cytoplasm through endocytosis or direct membrane fusion (1). The positive-sense RNA genome is translated by the host translation machinery (2) to make polyproteins that are cotranslationally cleaved by proteases encoded in the polyprotein to generate components of RdRp complex (3). The RdRp complex uses the genome as a template to generate negative-sense subgenome and genome-length RNAs (4), which are in turn used as templates for synthesis of positive-sense full-length progeny genomes and subgenomic mRNAs (5). Transcription and replication occur in convoluted membranes (CM) adjacent to DMVs that are both derived from rough endoplasmic reticulum. The subgenomic mRNAs are translated into structural and accessory proteins (6). The positive sense genomic RNA is bound by nucleocapsid and buds into the ERGIC, which is decorated with structural proteins S, E, and M translated from positive-sense subgenomic RNAs (steps 6 and 7). The enveloped virion is then exported from the cell by exocytosis (steps 8 and 9).

S-CoV-2

Hartenian et al. J. Biol. Chem. 2020, 295, 12910-12934.

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ENZYME FUNCTION Cell entry Spike protein trimer

The SARS-CoV-2 S protein engages with the host ACE2 receptor and is subsequently cleaved at S1/S2 and S2′ sites by TMPRSS2 protease. This leads to activation of the S2 domain and drives fusion of the viral and host membranes. See section on 'viral entry' for details. ACE2 = Angiotensin-converting enzyme 2 TMPRSS = Transmembrane protease, serine 2 Wikipedia

Hartenian et al. J. Biol. Chem. 2020, 295, 12910-12934.

RBD = Receptor Binding Domain

Dömling and Gao Chem. 2020, 6, 1283-1295.

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SARS-CoV-2 polyproteins

Hartenian et al. J. Biol. Chem. 2020, 295, 12910-12934.

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SARS-CoV-2 polyproteins

Ullrich and Nitsche Bioorg. Med. Chem. Lett. 2020, 30, 127377.

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Cysteine protease SARS-CoV-2 main protease Homodimer 3 Domains

Ullrich and Nitsche Bioorg. Med. Chem. Lett. 2020, 30, 127377.

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ENZYME FUNCTION Cysteine protease – catalytic dyad

I +R-CONH-R’

H N

S O

H N

II S

HN

N

O

SH

H N NH HN

HN

V

Substrate hydrolysis I: Thiol deprotonation II: Nucleophilic attack III: Release of amine IV: Thioester hydrolysis V: Release of carboxylic acid

-R-COOH

S O

OH

-R’-NH2 +H2O

H N

S O

HN

N H

O

H

HN

IV

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III

SARS-CoV-2 main protease inhibitors

Zhang et al. Science 2020, 368, 409412.

Jin et al. Nature 293.

2020, 582, 289-

Ullrich and Nitsche Bioorg. Med. Chem. Lett. 2020, 30, 127377.

Dai et al. Science 2020, 368, 13311335.

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