Placeholder image of a protein
Icon representing a puzzle

971c: Ebola glycoprotein peptide inhibitor design

Closed since over 11 years ago

Intermediate Overall Design

Summary

Created
August 20, 2014
Expires
Max points
100
Description

We would like you to design a small (25-residue) peptide that can bind to and block the Ebola glycoprotein. The glycoprotein is a viral surface protein that allows the Ebola virus to enter human cells. A small peptide inhibitor of this protein would therefore represent a candidate therapeutic for treating this deadly disease. We are starting you with a hotspot "stub" that was the top-scoring result from the earlier stub-finding puzzle, number 846. (Congratulations to AnthropicDreams!) We have extended this stub with twenty-two additional residues that you can design. A small peptide in this size range probably won't fold the way a protein would. Some considerations -- good hydrophobic packing, lack of holes in the core, good hydrogen bonding, presence of secondary structure, etc. -- will be the same, but in addition, heavy disulfide cross-linking is often necessary for stability in this size range. You will get a considerable bonus for forming up to three disulfide bonds (for a total of five, counting the two disulfide bonds already present in the Ebola target protein). Many natural plant and animal toxins are small peptides, and it is common to see three disulfide bonds in a "leapfrog" pattern (i.e. cys1-cys4, cys2-cys5, cys3-cys6) for maximal stability. The starting point for this puzzle has three disulfides in this "leapfrog" pattern, but this might not be the optimal disulfide placement or backbone topology. Feel free to change the secondary structure, move the disulfides around, or otherwise improve on this!

Top groups

  1. Avatar for Anthropic Dreams
    1. Anthropic Dreams
    100 pts. 13,261
  2. Avatar for Go Science 2. Go Science 83 pts. 13,255
  3. Avatar for Void Crushers 3. Void Crushers 69 pts. 13,009
  4. Avatar for Beta Folders 4. Beta Folders 56 pts. 13,003
  5. Avatar for Contenders 5. Contenders 45 pts. 13,000
  6. Avatar for L'Alliance Francophone 6. L'Alliance Francophone 36 pts. 12,970
  7. Avatar for Repro-men 7. Repro-men 29 pts. 12,945
  8. Avatar for Gargleblasters 8. Gargleblasters 23 pts. 12,897
  9. Avatar for Deleted group 9. Deleted group pts. 12,851
  10. Avatar for Italiani Al Lavoro 10. Italiani Al Lavoro 14 pts. 12,832
  1. Avatar for alcor29 61. alcor29 Lv 1 41 pts. 12,774
  2. Avatar for jugemu 62. jugemu Lv 1 40 pts. 12,773
  3. Avatar for pizpot 63. pizpot Lv 1 39 pts. 12,771
  4. Avatar for Hiro Protagonist 64. Hiro Protagonist Lv 1 39 pts. 12,769
  5. Avatar for frood66 65. frood66 Lv 1 38 pts. 12,769
  6. Avatar for perrystaff 66. perrystaff Lv 1 37 pts. 12,767
  7. Avatar for bamh 67. bamh Lv 1 37 pts. 12,767
  8. Avatar for Jim Fraser 68. Jim Fraser Lv 1 36 pts. 12,762
  9. Avatar for Maverick314 69. Maverick314 Lv 1 35 pts. 12,757
  10. Avatar for SamuelJackson 70. SamuelJackson Lv 1 35 pts. 12,754

Comments

wisky Lv 1

I would like to see this puzzle in different sizes, like 25, 35, and 45 residues with the 3 cystine bond pattern requirement! I think that would give you guys a nice big set of good designs to pick from.

Susume Lv 1

There's more info and diagrams for some "leapfrog" disulfide patterns here: http://www.cyclotide.com/knots.html

The page says cystine knots are 26-48 residues long, so 25 may be at the lower limit of what will fold up that way. I agree with wisky - I'd like to work on longer versions too.

v_mulligan Lv 1

I know that 25 residues is definitely a challenge. We picked this size for two reasons: first, it's in a size range that is nicely compatible with chemical synthesis. Large proteins must be expressed in bacteria or yeast, but with a small enough peptide, we have the option of artificially synthesizing the peptide. This allows for inclusion of nonstandard amino acids and other unnatural modifications that can add new functionality, as well as for large-scale production of fairly pure peptide. Unfortunately, the longer the peptide, the harder it is to synthesize and get good yields and high purity. I wanted to keep the peptide short enough that synthesis is a very feasible option.

Second, where large proteins are difficult to get into the body and difficult to get across barriers, a sufficiently small peptide (particularly if compact and ordered) has the potential for oral bioavailability, which makes it easier to use as a drug.

In short, if we keep it small, we might have some of the advantages of both small-molecule drugs (which get into the body easily and are easy to produce in large amounts, but which are usually pretty nonspecific) and proteins (which can have terrific specificity and affinity for a target, meaning a potent desired effect with few side-effects, but which don't get into the body easily). That's the hope, anyways!