Chemistry Reference
In-Depth Information
comparable to the approved N(t)RTI 1 toward wt virus and host polymerases,
but with an improved resistance profile.
10.2.4 Clinical Isolate Resistance Profiling
The encouraging resistance profile of 22 justified more extensive profiling
toward a panel of N(t)RTI-resistant patient isolates.
29
The Manhattan plot
shown in Figure 10.5 compares the fold resistance of 22 and several marketed
N(t)RTIs toward a panel of isolates containing the major known RT resistance
mutations (M184V, K65R, multiple TAMs, L74V, and others) and their
clinically relevant combinations.
Compared to all the N(t)RTIs in clinical use, 22 has an improved resistance
profile with
o
3-fold change in susceptibility to all but one isolate. In the HIV
RT model, the inhibitor binds in a similar orientation to dATP. Since 22-DP is
similar in size and shape to the natural substrate, it would be expected that RT
mutations in the active site that discriminate against 22-DP, whilst still
retaining ecient incorporation of the natural dATP substrate, may be dicult
to obtain. Ecient utilization of the natural substrates is of course necessary
for the virus to remain fit and viable. The multi-drug-resistant mutation
complex containing Q151M demonstrated the most significant reduction in
susceptibility toward 22. This was slightly worse than 1 but not as poor as most
of the other NRTIs shown in Figure 10.5. The 2
0
-F group of 22 lies in close
proximity to the side-chain of residue Q151 of RT shown in Figure 10.4 and
provides a rationale for how mutations at residue Q151 could lead to resistance.
Subsequent to the completion of this research program, the X-ray structure of
30
25
20
15
10
5
0
7 (ABC)
6 (ddI)
3 (FTC)
ddI)
1 (TFV)
22 (GS-9148)
-
Figure 10.5
Resistance profile of 22 and other N(t)RTI toward patient isolates
(Monogram Biosciences).
Search WWH ::
Custom Search