# Making the HIV-1 gp41 pocket amenable to small-molecule drug discovery

> **NIH NIH DP1** · STANFORD UNIVERSITY · 2020 · $785,000

## Abstract

The long-term objective of the research proposed here is to set the stage for the discovery of a 
new class of orally bioavailable, small-molecule drugs that target the HIV-1 gp41 pocket. Because 
the residues that form the gp41 pocket are extremely highly conserved, such drugs are predicted to 
have broad-spectrum activity and be relatively resistant to the development of “escape” mutations. 
This new class of drugs could be particularly useful in patients with viruses that have developed 
resistance to one or more classes of anti-HIV drugs.
Earlier, cyclic D-peptides inhibitors of HIV-1 were isolated that bind to the gp41 pocket. However, 
in spite of numerous efforts in academia and industry over the past ~15 years, there are no 
small-molecule HIV-1 inhibitors targeting the gp41 pocket in clinical development.
Indeed, the gp41 pocket has been referred to as an “undruggable” target.
Analysis of the structures of the gp41 pocket bound to different protein and peptide ligands 
indicate that the gp41 pocket is highly malleable. We hypothesize that it is more difficult to 
identify good small-molecule drug leads for a target that is malleable, as compared to a target 
that is rigid. We also hypothesize that establishing useful structure-activity relationships (SARs) 
for chemical analogs of drug leads will be more difficult with a malleable target, as compared to a 
rigid target.
We propose several approaches to “rigidify” the gp41 pocket. After we have created a rigidified 
gp41 pocket(s), we will test predictions based on the two hypotheses above. First, we predict that 
a high-throughput screen (HTPS) with a rigid gp41 pocket will yield better hit rates than the 
malleable pocket. Second, we predict that we will be able to more readily establish useful SARs 
with a rigid gp41 pocket than with a malleable one.
Ligands identified in this manner are expected to have weaker affinity for the natural (i.e., 
malleable) gp41 pocket, as compared to the rigidified pocket. In essence, the binding affinity will 
be decreased by the energy necessary to lock the natural gp41 pocket into a fixed conformation. The 
key point, however, is that by increasing the success of HTPS efforts and obtaining useful SARs 
(with the rigid gp41 pocket), it will be possible to optimize binding affinity of the 
small-molecule hits by medicinal chemistry, so that the energetic cost of locking the natural gp41 
pocket into a fixed conformation can be readily paid.

## Key facts

- **NIH application ID:** 9868969
- **Project number:** 5DP1DA043893-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** PETER S KIM
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $785,000
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868969

## Citation

> US National Institutes of Health, RePORTER application 9868969, Making the HIV-1 gp41 pocket amenable to small-molecule drug discovery (5DP1DA043893-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9868969. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*