From Molecules to Medicine: How Structure Helps Cure

10/9/2014

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Co-produced with the American Crystallographic Association A

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ACA History through photos! A) William Lipscomb and Herbert Hauptman at an IUCr Congress and General Assembly. B) Irving Langmuir, J.D. Bernal and Dorothy Hodgkin at the 1937 British Association Meeting. C) Walter Hamilton, Helen Berman, and Tom Koetzle on their way to a meeting in Aarhus in 1972.

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“From Molecules to Medicine: How Structure Helps Cure Disease”

Dr. Martha Teeter President, American Crystallographic Association

Dr. Greg Petsko Professor of Neurology, Weill Cornell Medical College

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From Molecules To Medicines: How Structure Helps Cure Disease

Amyloidogenic NonAmyloidogenic

APP

Gregory A. Petsko Appel Alzheimer’s Disease Research Institute Weill Cornell Medical College, New York, NY 10021 USA

Structural Age Of In 2013 in Biology the U.S.,In onThe average… Genomics EVERY APPROVED DRUG REQUIRES

- Synthesis of 6,200 chemical compounds - 21 compounds tested in subacute toxicology - 7 compounds tested in humans - 3 compounds in Phase III clinical trials - 13 years and $450 $850 million

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Audience Survey Question

Where do most drugs candidates fail? • Phase I (toxicity) • Phase II (efficacy) • Phase III (head-to-head against best available therapy) • Junior High

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The Answer

Most drugs (~60%) fail in Phase II (efficacy)!

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Why do most drugs fail in Phase II? • They don’t hit the intended target • They have poor bioavailability • The target is not a valid target for the human disease • They didn’t study for the test

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The Answer The target is not a valid target for the human disease. What this means: Our animal models for toxicity and pharmacokinetics are pretty good. Our animal models for disease are not.

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Alzheimer’s Disease Incidence is >300,000 cases/yr in the USA – One every 4 seconds worldwide Prevalence is 5,500,000 in USA Mean survival after diagnosis is ~10 years

10% of cases are genetic; rest are sporadic and idiopathic Current drug market is ~$10 billion First gene discovered was APP; now more than 5 others. Most important are APP and presenilin (γ-secretase). Most important risk factors are ApoE2 (protective) and ApoE4 (increased risk). APP A563T mutation is also protective


What is the fastest-growing demographic group in the United States? • • • •

Children Young adults Octogenarians and older Unemployed PhDs

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The Answer: Octogenarians and Above

National Vital Statistics Report, Feb. 2001

The Problem With Living Longer

Alzheimer’s Disease

Parkinson’s Disease

ALS

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Alois Alzheimer

Auguste Deter

Plaques and Tangles in the Brain of Auguste Deter

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Neurodegenerative diseases are characterized by dense aggregates of misfolded proteins

AD β-amyloid

PD or LBD α-synuclein

AD or FTD tau

ALS or FTD TDP-43

ALS SOD1

ALS or FTD FUS

What is the toxic species?

tau

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Most significant change in vulnerable brain regions in early AD VPS35 (Vacuolar Protein Sorting gene 35) Originally discovered in yeast Involved in protein trafficking Conserved in all eukaryotes Component of the retromer multiprotein complex All components are down by 2-3x in Vulnerable brain regions in early AD

BACE1

Retromer

Images Courtesy of Shutterstock

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Too little retromer

Retromer


Retromer overexpression

Retromer


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Stabilization of Unstable Mutant Forms of Glucocerebrosidase as a Therapeutic Approach for Gaucher Disease

Lieberman et al., Nat. Chem. Biol. (2007)

The MSCS Method Can Map the Binding Surface of any Crystalline Protein

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Finding Protein Ligands by in Silico Screening 3D structure of target

Library of >14 million compound structures

Screen top ~200 predicted ligands based on calculated interaction energy

With thanks to Tack Kuntz and Brian Shoichet


In silico screening (docking) can increase the hit rate of a subsequent real screen by: • • • •

10-50x 100-300x 1,000–5,000x 0; it doesn’t help at all

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The Answer In silico screening (docking) can increase the hit rate of a subsequent real screen by 1,000–5,000x Typically, it s only necessary to screen the top 100-200 predicted binders for real in order to get 5-10 compounds that actually bind

VPS29/35 Interface: The Weak Link -VPS35 protein levels are decreased in Alzheimer’s -Weakest link in Retromer structure is interface with 29

A. Hierro et al. 2007

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VPS35/VPS29 Complex

The Retromer Core Complex (VPS35, VPS26 and VPS29) unfolds at ~49oC

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Inactive Compound Titration 1.2

1

Fraction Protein Unfolded

0.8 2 mM 1 mM 0.5 mM 0.6

0.25 mM 0.125 mM 62.5 uM 31.25 uM 15.625 uM

0.4

No Compound

0.2

0 0

10

20

30

40 50 60 Temperature (Celcius)

70

80

90

100

Retromer with Best Compound (R55): a 10oC Stabilization

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Dramatic R55-dependent Reduction in the Amount of APP in Late Endosomes

R55

Human Molecular Genetics, 2012

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R55 Lowers Aβ Levels in Cortical Neurons from an Alzheimer’s Patient

R55 Lowers Level of Aβ in a Dosedependent Manner

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R55 Increase in Retromer Level is Inversely Correlated with Level of Aβ

Fragment Pattern is Exactly as Predicted

R55

βCTF

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Retromer Link to Familial Parkinson’s Disease The American Journal of Human Genetics 89, 162–167, July 15, 2011

The American Journal of Human Genetics 89, 168–175, July 15, 2011

VPS35 Expression is Reduced in the Substantia Nigra and Cerebral Cortex of PD Patients

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• We have previously reported that overexpression of VPS35 rescues defects observed in LRRK2 G2019S models both in vitro and in cultured rodent neurons (shortened neurites, trafficking defects, and lysosomal abnormalities). •

MacLeod, D.A., Rhinn, H., Kuwahara, T., Zolin, A., Di Paolo, G., McCabe, B.D., Marder, K.S., Honig, L.S., Clark, L.N., Small, S.A., et al. (2013). RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk. Neuron 77, 425-439.

•

Do the retromer pharmacological chaperones do the same?

R55 Rescues Primary Neurons in Rat Models of VPS35 and LRRK2-dependent PD

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Dagmar Ringe

Vincent Mecozzi

Scott Small

Asa Abeliovich

Shulin Ju

Diego Berman

Further Reading Mecozzi VJ, Berman DE, Simoes S, Vetanovetz C, Awal MR, Patel VM, Schneider RT, Petsko GA, Ringe D, Small SA. “Pharmacological chaperones stabilize retromer to limit APP processing.” Nature Chem Biol. Apr 20. 10:443-449 (2014). Petsko, GA. “The Coming Epidemic of Neurologic Disorders: What Science Is – and Should Be – Doing About It.” Daedalus, Summer 2012, Vol. 141, No. 3, Pages 98-107 Ringe D, Petsko GA. “What are pharmacological chaperones and why are they interesting?” J Biol. (now BMC Biology) 8(9):80-83 (2009). Landon MR, Lieberman RL, Hoang QQ, Ju S, Caaveiro JM, Orwig SD, Kozakov D, Brenke R, Chuang GY, Beglov D, Vajda S, Petsko GA, Ringe D. “Detection of ligand binding hot spots on protein surfaces via fragment-based methods: application to DJ-1 and glucocerebrosidase.” J Comput Aided Mol Des. 23[8]:491-500 (2009). Lieberman RL, D'aquino JA, Ringe D, Petsko GA. “Effects of pH and iminosugar pharmacological chaperones on lysosomal glycosidase structure and stability.” Biochemistry. 48(22):4816-4827 (2009). Lieberman RL, Wustman BA, Huertas P, Powe AC Jr, Pine CW, Khanna R, Schlossmacher MG, Ringe D, Petsko GA. “Structure of acid beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease.” Nature Chem Biol. 3(2):101-107 (2007). Ringe, D. and Petsko, G.A. "The Age of Structure: The Role of Protein Crystallography in Drug Design", New Perspectives in Drug Design, Academic Press Ltd. (1995).

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Dr. Martha Teeter

Dr. Greg Petsko

President, American Crystallographic Association

Professor of Neurology, Weill Cornell Medical College



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Co-produced with the American Crystallographic Association A

B

ACA History through photos! A) William Lipscomb and Herbert Hauptman at an IUCr Congress and General Assembly. B) Irving Langmuir, J.D. Bernal and Dorothy Hodgkin at the 1937 British Association Meeting. C) Walter Hamilton, Helen Berman, and Tom Koetzle on their way to a meeting in Aarhus in 1972.

C

D

D) Richard E. Marsh and Linus Pauling, at Caltech during Pauling's 85th birthday celebration in 1986.

Photo Credit: ACA

www.amercrystalassn.org

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Dr. Martha Teeter President, American Crystallographic Association

Dr. Greg Petsko Professor of Neurology, Weill Cornell Medical College



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From Molecules to Medicine: How Structure Helps Cure

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